1N0W , 1B22
149-525: 5888 19361 ENSG00000051180 n/a Q06609 Q08297 NM_001164269 NM_001164270 NM_002875 NM_133487 NM_011234 NP_001157741 NP_001157742 NP_002866 NP_597994 NP_035364 DNA repair protein RAD51 homolog 1 is a protein encoded by the gene RAD51 . The enzyme encoded by this gene is a member of the RAD51 protein family which assists in repair of DNA double strand breaks . RAD51 family members are homologous to
298-479: A histone deacetylase (HDAC) inhibitor specific for SIRT1 , an HDAC specific for H4K16. Other histone marks associated with tumorigenesis include increased deacetylation (decreased acetylation) of histones H3 and H4, decreased trimethylation of histone H3 Lysine 4 ( H3K4me3 ), and increased monomethylation of histone H3 Lysine 9 ( H3K9me1 ) and trimethylation of histone H3 Lysine 27 ( H3K27me3 ). These histone modifications can silence tumor suppressor genes despite
447-419: A histone deacetylase that acts on many histone-tail lysines , has been associated with cancers showing altered histone acetylation patterns. These findings indicate a promising mechanism for altering epigenetic profiles through enzymatic inhibition or enhancement. A new emerging field that captures toxicological epigenetic changes as a result of the exposure to different compounds (drugs, food, and environment)
596-584: A promoter sequence. The promoter is recognized and bound by transcription factors that recruit and help RNA polymerase bind to the region to initiate transcription. The recognition typically occurs as a consensus sequence like the TATA box . A gene can have more than one promoter, resulting in messenger RNAs ( mRNA ) that differ in how far they extend in the 5' end. Highly transcribed genes have "strong" promoter sequences that form strong associations with transcription factors, thereby initiating transcription at
745-596: A " start codon ", and three " stop codons " indicate the beginning and end of the protein coding region . There are 64 possible codons (four possible nucleotides at each of three positions, hence 4 possible codons) and only 20 standard amino acids; hence the code is redundant and multiple codons can specify the same amino acid. The correspondence between codons and amino acids is nearly universal among all known living organisms. Cancer epigenetics#Frequencies of epimutations in DNA repair genes Cancer epigenetics
894-413: A DSB, MRE11 - RAD50 - NBS1 (MRN) protein complex recruits ataxia telangiectasia mutated (ATM) kinase which phosphorylates Serine 129 of Histone 2A. MDC1, mediator of DNA damage checkpoint 1, binds to the phosphopeptide, and phosphorylation of H2AX may spread by a positive feedback loop of MRN-ATM recruitment and phosphorylation. TIP60 acetylates the γH2AX , which is then polyubiquitylated . RAP80 ,
1043-626: A broader diversity of related recombinase paralogs are found in Crenarchaea , including Ral1, Ral2, Ral3, RadC, RadC1, and RadC2. The RAD51 paralogs contribute to efficient DNA double-strand break repair by homologous recombination . Consequently, experimental depletion of these paralogs often result in significantly reduced homologous recombination. The paralogs form two identified complexes: BCDX2 (RAD51B-RAD51C-RAD51D-XRCC2) and CX3 (RAD51C-XRCC3). These two complexes act at two different stages of homologous recombinational DNA repair . The BCDX2 complex
1192-737: A causal factor. In 29–66% of glioblastomas , DNA repair is deficient due to epigenetic methylation of the MGMT gene, which reduces protein expression of MGMT. High mobility group A ( HMGA ) proteins, characterized by an AT-hook , are small, nonhistone, chromatin-associated proteins that can modulate transcription. MicroRNAs control the expression of HMGA proteins, and these proteins ( HMGA1 and HMGA2 ) are architectural chromatin transcription-controlling elements. Palmieri et al. showed that, in normal tissues, HGMA1 and HMGA2 genes are targeted (and thus strongly reduced in expression) by miR-15 , miR-16 , miR-26a , miR-196a2 and Let-7a . HMGA expression
1341-580: A cell's transformation to cancer. The disturbance of epigenetic processes in cancers, can lead to a loss of expression of genes that occurs about 10 times more frequently by transcription silencing (caused by epigenetic promoter hypermethylation of CpG islands ) than by mutations. As Vogelstein et al. points out, in a colorectal cancer there are usually about 3 to 6 driver mutations and 33 to 66 hitchhiker or passenger mutations. However, in colon tumors compared to adjacent normal-appearing colonic mucosa, there are about 600 to 800 heavily methylated CpG islands in
1490-638: A cell-cycle inhibitor; MGMT , a DNA repair gene; APC , a cell cycle regulator; MLH1 , a DNA-repair gene; and BRCA1 , another DNA-repair gene. Indeed, cancer cells can become addicted to the transcriptional silencing, due to promoter hypermethylation, of some key tumor suppressor genes, a process known as epigenetic addiction. Hypomethylation of CpG dinucleotides in other parts of the genome leads to chromosome instability due to mechanisms such as loss of imprinting and reactivation of transposable elements . Loss of imprinting of insulin-like growth factor gene (IGF2) increases risk of colorectal cancer and
1639-445: A continuous messenger RNA , referred to as a polycistronic mRNA . The term cistron in this context is equivalent to gene. The transcription of an operon's mRNA is often controlled by a repressor that can occur in an active or inactive state depending on the presence of specific metabolites. When active, the repressor binds to a DNA sequence at the beginning of the operon, called the operator region , and represses transcription of
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#17328548205571788-542: A correlation exists between CIN3+ and increased methylation of CpG sites in the HPV16 L1 open reading frame. This could be a potential biomarker for future screens of cancerous and precancerous cervical disease. Recent studies have shown that the mixed-lineage leukemia (MLL) gene causes leukemia by rearranging and fusing with other genes in different chromosomes, which is a process under epigenetic control. Mutations in MLL block
1937-491: A decrease in histone H4R3 asymmetric dimethylation (H4R3me2a) of the p19ARF promoter is correlated with more advanced cases of tumorigenesis and metastasis. In mouse models, the loss of histone H4 acetylation and trimethylation increases as tumor growth continues. Loss of histone H4 Lysine 16 acetylation ( H4K16ac ), which is a mark of aging at the telomeres , specifically loses its acetylation. Some scientists hope this particular loss of histone acetylation might be battled with
2086-443: A deficiency in DNA repair is occasionally found to be due to a mutation in a DNA repair gene, but much more frequently reduced or absent expression of DNA repair genes is due to epigenetic alterations that reduce or silence gene expression. For example, for 113 colorectal cancers examined in sequence, only four had a missense mutation in the DNA repair gene MGMT , while the majority had reduced MGMT expression due to methylation of
2235-449: A double-helix run in opposite directions. Nucleic acid synthesis, including DNA replication and transcription occurs in the 5'→3' direction, because new nucleotides are added via a dehydration reaction that uses the exposed 3' hydroxyl as a nucleophile . The expression of genes encoded in DNA begins by transcribing the gene into RNA , a second type of nucleic acid that is very similar to DNA, but whose monomers contain
2384-488: A few genes and are transferable between individuals. For example, the genes for antibiotic resistance are usually encoded on bacterial plasmids and can be passed between individual cells, even those of different species, via horizontal gene transfer . Whereas the chromosomes of prokaryotes are relatively gene-dense, those of eukaryotes often contain regions of DNA that serve no obvious function. Simple single-celled eukaryotes have relatively small amounts of such DNA, whereas
2533-540: A formulation of 5-azacitidine (an unmethylatable analog of cytidine that causes hypomethylation when incorporated into DNA) states that "men should be advised not to father a child" while using the drug, citing evidence in treated male mice of reduced fertility, increased embryo loss , and abnormal embryo development. In rats, endocrine differences were observed in offspring of males exposed to morphine. In mice, second generation effects of diethylstilbesterol have been described occurring by epigenetic mechanisms. Melanoma
2682-434: A gene - surprisingly, there is no definition that is entirely satisfactory. A gene is a DNA sequence that codes for a diffusible product. This product may be protein (as is the case in the majority of genes) or may be RNA (as is the case of genes that code for tRNA and rRNA). The crucial feature is that the product diffuses away from its site of synthesis to act elsewhere. The important parts of such definitions are: (1) that
2831-565: A gene corresponds to a transcription unit; (2) that genes produce both mRNA and noncoding RNAs; and (3) regulatory sequences control gene expression but are not part of the gene itself. However, there's one other important part of the definition and it is emphasized in Kostas Kampourakis' book Making Sense of Genes . Therefore in this book I will consider genes as DNA sequences encoding information for functional products, be it proteins or RNA molecules. With 'encoding information', I mean that
2980-410: A gene may be split across chromosomes but those transcripts are concatenated back together into a functional sequence by trans-splicing . It is also possible for overlapping genes to share some of their DNA sequence, either on opposite strands or the same strand (in a different reading frame, or even the same reading frame). In all organisms, two steps are required to read the information encoded in
3129-404: A gene's DNA and produce the protein it specifies. First, the gene's DNA is transcribed to messenger RNA ( mRNA ). Second, that mRNA is translated to protein. RNA-coding genes must still go through the first step, but are not translated into protein. The process of producing a biologically functional molecule of either RNA or protein is called gene expression , and the resulting molecule
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#17328548205573278-565: A gene: that of bacteriophage MS2 coat protein. The subsequent development of chain-termination DNA sequencing in 1977 by Frederick Sanger improved the efficiency of sequencing and turned it into a routine laboratory tool. An automated version of the Sanger method was used in early phases of the Human Genome Project . The theories developed in the early 20th century to integrate Mendelian genetics with Darwinian evolution are called
3427-439: A gene; however, members of a population may have different alleles at the locus, each with a slightly different gene sequence. The majority of eukaryotic genes are stored on a set of large, linear chromosomes. The chromosomes are packed within the nucleus in complex with storage proteins called histones to form a unit called a nucleosome . DNA packaged and condensed in this way is called chromatin . The manner in which DNA
3576-424: A high frequency of mutations . A high frequency of genomic mutations increases the likelihood of particular mutations occurring that activate oncogenes and inactivate tumor suppressor genes, leading to carcinogenesis . On the basis of whole genome sequencing , cancers are found to have thousands to hundreds of thousands of mutations in their whole genomes. (Also see Mutation frequencies in cancers .) By comparison,
3725-448: A high rate. Others genes have "weak" promoters that form weak associations with transcription factors and initiate transcription less frequently. Eukaryotic promoter regions are much more complex and difficult to identify than prokaryotic promoters. Additionally, genes can have regulatory regions many kilobases upstream or downstream of the gene that alter expression. These act by binding to transcription factors which then cause
3874-672: A key event leading to genomic instability and tumorigenesis. Several alterations of the Rad51 gene have been associated with an increased risk of developing breast cancer . The breast cancer susceptibility protein BRCA2 and PALB2 controls the function of Rad51 in the pathway for DNA repair by homologous recombination. In addition to the data listed in Table 1, increased RAD51 expression levels have been identified in metastatic canine mammary carcinoma, indicating that genomic instability plays an important role in
4023-443: A miRNA that functions as a tumor suppressor , was observed in prostate, ovarian , breast and glial cell cancers. In vitro experiments have shown that miR-125b1 targets two genes, HER2/neu and ESR1 , that are linked to breast cancer. DNA methylation, specifically hypermethylation, is one of the main ways that the miR-125b1 is epigenetically silenced. In patients with breast cancer, hypermethylation of CpG islands located proximal to
4172-1082: A molecular level, there are microenvironmental factors that can influence and effect metabolic recoding. These influences include nutritional, inflammatory, and the immune response of malignant tissues. DNA damage appears to be the primary underlying cause of cancer. If DNA repair is deficient, DNA damage tends to accumulate. Such excess DNA damage can increase mutational errors during DNA replication due to error-prone translesion synthesis . Excess DNA damage can also increase epigenetic alterations due to errors during DNA repair. Such mutations and epigenetic alterations can give rise to cancer (see malignant neoplasms ). Germ line mutations in DNA repair genes cause only 2–5% of colon cancer cases. However, altered expression of microRNAs, causing DNA repair deficiencies, are frequently associated with cancers and may be an important causal factor for these cancers. Over-expression of certain miRNAs may directly reduce expression of specific DNA repair proteins. Wan et al. referred to 6 DNA repair genes that are directly targeted by
4321-454: A much broader diversity of Rad51 recombinase paralog proteins exist. In budding yeast ( Saccharomyces cerevisiae ), the paralogs Rad55 and Rad57 form a complex that associates with Rad51 at ssDNA. The recombinase paralog rfs-1 is found in the round worm Caenorhabditis elegans , however it is not essential for homologous recombination. Among archaea , RadB and RadC recombinase paralogs are found in many organisms belonging to Euryarchaeota , while
4470-415: A mutation with a selective advantage. A clonal patch with a selective advantage may grow and out-compete neighboring cells, forming a field defect . While there is no obvious selective advantage for a cell to have reduced DNA repair, the epimutation of the DNA repair gene may be carried along as a passenger when the cells with the selectively advantageous mutation are replicated. In the cells carrying both
4619-572: A new expanded definition that includes noncoding genes. However, some modern writers still do not acknowledge noncoding genes although this so-called "new" definition has been recognised for more than half a century. Although some definitions can be more broadly applicable than others, the fundamental complexity of biology means that no definition of a gene can capture all aspects perfectly. Not all genomes are DNA (e.g. RNA viruses ), bacterial operons are multiple protein-coding regions transcribed into single large mRNAs, alternative splicing enables
RAD51 - Misplaced Pages Continue
4768-461: A number of these diseases. In somatic cells, patterns of DNA methylation are in general transmitted to daughter cells with high fidelity. Typically, this methylation only occurs at cytosines that are located 5' to guanosine in the CpG dinucleotides of higher order eukaryotes. However, epigenetic DNA methylation differs between normal cells and tumor cells in humans. The "normal" CpG methylation profile
4917-414: A part in silencing the gene. Furthermore, some miRNA's are epigenetically silenced early on in breast cancer, and therefore these miRNA's could potentially be useful as tumor markers. The epigenetic silencing of miRNA genes by aberrant DNA methylation is a frequent event in cancer cells; almost one third of miRNA promoters active in normal mammary cells were found hypermethylated in breast cancer cells - that
5066-400: A process known as RNA splicing . Finally, the ends of gene transcripts are defined by cleavage and polyadenylation (CPA) sites , where newly produced pre-mRNA gets cleaved and a string of ~200 adenosine monophosphates is added at the 3' end. The poly(A) tail protects mature mRNA from degradation and has other functions, affecting translation, localization, and transport of the transcript from
5215-419: A protein-coding gene consists of many elements of which the actual protein coding sequence is often only a small part. These include introns and untranslated regions of the mature mRNA. Noncoding genes can also contain introns that are removed during processing to produce the mature functional RNA. All genes are associated with regulatory sequences that are required for their expression. First, genes require
5364-412: A single genomic region to encode multiple district products and trans-splicing concatenates mRNAs from shorter coding sequence across the genome. Since molecular definitions exclude elements such as introns, promotors, and other regulatory regions , these are instead thought of as "associated" with the gene and affect its function. An even broader operational definition is sometimes used to encompass
5513-499: A source of the increased epigenetic alterations found in many genes in cancers. In an early study, looking at a limited set of transcriptional promoters, Fernandez et al. examined the DNA methylation profiles of 855 primary tumors. Comparing each tumor type with its corresponding normal tissue, 729 CpG island sites (55% of the 1322 CpG sites evaluated) showed differential DNA methylation. Of these sites, 496 were hypermethylated (repressed) and 233 were hypomethylated (activated). Thus, there
5662-472: A strict definition of the word "gene" with which nearly every expert can agree. First, in order for a nucleotide sequence to be considered a true gene, an open reading frame (ORF) must be present. The ORF can be thought of as the "gene itself"; it begins with a starting mark common for every gene and ends with one of three possible finish line signals. One of the key enzymes in this process, the RNA polymerase, zips along
5811-539: A strong increase of HMGA1a and HMGA1b proteins. Transgenic mice with HMGA1 targeted to lymphoid cells develop aggressive lymphoma, showing that high HMGA1 expression is not only associated with cancers, but that the HMGA1 gene can act as an oncogene to cause cancer. Baldassarre et al., showed that HMGA1 protein binds to the promoter region of DNA repair gene BRCA1 and inhibits BRCA1 promoter activity. They also showed that while only 11% of breast tumors had hypermethylation of
5960-672: A subunit of the DNA repair breast cancer type 1 susceptibility protein complex ( BRCA1 -A), binds ubiquitin attached to histones. BRCA1-A activity arrests the cell cycle at the G2/M checkpoint , allowing time for DNA repair, or apoptosis may be initiated. In mammals, microRNAs (miRNAs) regulate about 60% of the transcriptional activity of protein-encoding genes. Some miRNAs also undergo methylation-associated silencing in cancer cells. Let-7 and miR15/16 play important roles in down-regulating RAS and BCL2 oncogenes , and their silencing occurs in cancer cells. Decreased expression of miR-125b1,
6109-409: A true gene, by this definition, one has to prove that the transcript has a biological function. Early speculations on the size of a typical gene were based on high-resolution genetic mapping and on the size of proteins and RNA molecules. A length of 1500 base pairs seemed reasonable at the time (1965). This was based on the idea that the gene was the DNA that was directly responsible for production of
RAD51 - Misplaced Pages Continue
6258-466: Is a deadly skin cancer that originates from melanocytes. Several epigenetic alterations are known to play a role in the transition of melanocytes to melanoma cells. This includes DNA methylation that can be inherited without making changes to the DNA sequence, as well as silencing the tumor suppressor genes in the epidermis that have been exposed to UV radiation for periods of time. The silencing of tumor suppressor genes leads to photocarcinogenesis which
6407-556: Is a high level of epigenetic promoter methylation alterations in tumors. Some of these epigenetic alterations may contribute to cancer progression. A variety of compounds are considered as epigenetic carcinogens —they result in an increased incidence of tumors, but they do not show mutagen activity (toxic compounds or pathogens that cause tumors incident to increased regeneration should also be excluded). Examples include diethylstilbestrol , arsenite , hexachlorobenzene , and nickel compounds. Many teratogens exert specific effects on
6556-486: Is a several fold greater proportion than is usually observed for protein coding genes. Dysregulation of metabolism allows tumor cells to generate needed building blocks as well as to modulate epigenetic marks to support cancer initiation and progression. Cancer-induced metabolic changes alter the epigenetic landscape, especially modifications on histones and DNA, thereby promoting malignant transformation, adaptation to inadequate nutrition, and metastasis. In order to satisfy
6705-465: Is almost undetectable in differentiated adult tissues but is elevated in many cancers. HGMA proteins are polypeptides of ~100 amino acid residues characterized by a modular sequence organization. These proteins have three highly positively charged regions, termed AT hooks , that bind the minor groove of AT-rich DNA stretches in specific regions of DNA. Human neoplasias, including thyroid, prostatic, cervical, colorectal, pancreatic and ovarian carcinoma, show
6854-489: Is associated to epigenetic alterations in DNA methylation, DNA methyltransferases, and histone acetylation. These alterations are the consequence of deregulation of their corresponding enzymes. Several histone methyltransferases and demethylases are among these enzymes. Prostate cancer kills around 35,000 men yearly, and about 220,000 men are diagnosed with prostate cancer per year, in North America alone. Prostate cancer
7003-437: Is associated with Beckwith-Wiedemann syndrome which significantly increases the risk of cancer for newborns. In healthy cells, CpG dinucleotides of lower densities are found within coding and non-coding intergenic regions. Expression of some repetitive sequences and meiotic recombination at centromeres are repressed through methylation The entire genome of a cancerous cell contains significantly less methylcytosine than
7152-456: Is called a gene product . The nucleotide sequence of a gene's DNA specifies the amino acid sequence of a protein through the genetic code . Sets of three nucleotides, known as codons , each correspond to a specific amino acid. The principle that three sequential bases of DNA code for each amino acid was demonstrated in 1961 using frameshift mutations in the rIIB gene of bacteriophage T4 (see Crick, Brenner et al. experiment ). Additionally,
7301-857: Is caused by oncongenic human papillomavirus 16 ( HPV16 ). Furthermore, cervix intraepithelial neoplasia (CIN) is primarily caused by oncogenic HPV16. As in many cases, the causative factor for cancer does not always take a direct route from infection to the development of cancer. Genomic methylation patterns have been associated with invasive cervical cancer. Within the HPV16L1 region , 14 tested CpG sites have significantly higher methylation in CIN3+ than in HPV16 genomes of women without CIN3 . Only 2/16 CpG sites tested in HPV16 upstream regulatory region were found to have association with increased methylation in CIN3+. This suggests that
7450-403: Is caused by different oxidants or carcinogens . Real-time methylation-specific polymerase chain reaction (PCR) suggests that many other genes are also hypermethylated. Gene expression in the prostate may be modulated by nutrition and lifestyle changes. The second most common malignant tumor in women is invasive cervical cancer (ICC) and more than 50% of all invasive cervical cancer (ICC)
7599-548: Is considered the gold standard for measuring CpG methylation, when one of the other methods is used, results are usually confirmed using bisulfite sequencing[1]. Popular approaches for determining histone modification profiles in cancerous versus healthy cells include: Researchers are hoping to identify specific epigenetic profiles of various types and subtypes of cancer with the goal of using these profiles as tools to diagnose individuals more specifically and accurately. Since epigenetic profiles change, scientists would like to use
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#17328548205577748-530: Is deficient but the MGMT promoter is not methylated. In the glioblastomas without methylated MGMT promoters, the level of microRNA miR-181d is inversely correlated with protein expression of MGMT and the direct target of miR-181d is the MGMT mRNA 3'UTR (the three prime untranslated region of MGMT mRNA). Thus, in 28% of glioblastomas, increased expression of miR-181d and reduced expression of DNA repair enzyme MGMT may be
7897-576: Is detected in many cancers and is significantly associated with cellular proliferation and genomic instability. Histone variant macroH2A1 is important in the pathogenesis of many types of cancers, for instance in hepatocellular carcinoma. Other mechanisms include a decrease in H4K16ac may be caused by either a decrease in activity of a histone acetyltransferases (HATs) or an increase in deacetylation by SIRT1. Likewise, an inactivating frameshift mutation in HDAC2 ,
8046-820: Is epigenetically hypomethylated, and this contributes to progression to endometrial cancer, BRCA-mutated ovarian cancer, and BRCA-mutated serous ovarian cancer. Other genes in the MMEJ pathway are also over-expressed in a number of cancers (see MMEJ for summary), and are also shown in blue. Deficiencies in DNA repair proteins that function in accurate DNA repair pathways increase the risk of mutation. Mutation rates are strongly increased in cells with mutations in DNA mismatch repair or in homologous recombinational repair (HRR). Individuals with inherited mutations in any of 34 DNA repair genes are at increased risk of cancer (see DNA repair defects and increased cancer risk ). In sporadic cancers,
8195-460: Is generally also under-expressed in primary neuroblastomas . Table 2 summarizes these five microRNAs and the nature of their altered expression in cancers were it has been observed. Three other microRNAs have been identified, by various criteria, as likely to repress RAD51 (miR-96, miR-203, and miR-103/107). These microRNAs were then tested by over-expressing them in cells in vitro , and they were found to indeed repress RAD51 . This repression
8344-402: Is important in regulation of gene expression, yet cytosine methylation can lead directly to destabilizing genetic mutations and a precancerous cellular state. Methylated cytosines make hydrolysis of the amine group and spontaneous conversion to thymine more favorable. They can cause aberrant recruitment of chromatin proteins. Cytosine methylations change the amount of UV light absorption of
8493-667: Is involved in the search for homology and strand pairing stages of the process. Unlike other proteins involved in DNA metabolism, the RecA/Rad51 family forms a helical nucleoprotein filament on DNA. This protein can interact with the ssDNA-binding protein RPA , BRCA2 , PALB2 and RAD52 . The structural basis for Rad51 filament formation and its functional mechanism still remain poorly understood. However, recent studies using fluorescent labeled Rad51 have indicated that Rad51 fragments elongate via multiple nucleation events followed by growth, with
8642-624: Is likely due to Rad51’s central role in homologous recombinational repair of DNA damage. In mammals, microRNAs (miRNAs) regulate about 60% of the transcriptional activity of protein-encoding genes. Some miRNAs also undergo methylation-associated silencing in cancer cells. If a repressive miRNA is silenced by hypermethylation or deletion, then the gene it typically targets becomes over-expressed. At least eight miRNAs repressing RAD51 expression have been identified, with five of these appearing significant in cancer. For instance, in triple-negative breast cancers (TNBC), over-expression of miR-155
8791-400: Is nearly the same for all known organisms. The total complement of genes in an organism or cell is known as its genome , which may be stored on one or more chromosomes . A chromosome consists of a single, very long DNA helix on which thousands of genes are encoded. The region of the chromosome at which a particular gene is located is called its locus . Each locus contains one allele of
8940-558: Is often decreased. Hypermethylation of tumor suppressor gene promoter regions can result in silencing of those genes. This type of epigenetic mutation allows cells to grow and reproduce uncontrollably, leading to tumorigenesis. The addition of methyl groups to cytosines causes the DNA to coil tightly around the histone proteins, resulting in DNA that can not undergo transcription (transcriptionally silenced DNA). Genes commonly found to be transcriptionally silenced due to promoter hypermethylation include: Cyclin-dependent kinase inhibitor p16 ,
9089-461: Is often inverted in cells that become tumorigenic. In normal cells, CpG islands preceding gene promoters are generally unmethylated, and tend to be transcriptionally active, while other individual CpG dinucleotides throughout the genome tend to be methylated. However, in cancer cells, CpG islands preceding tumor suppressor gene promoters are often hypermethylated, while CpG methylation of oncogene promoter regions and parasitic repeat sequences
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#17328548205579238-534: Is responsible for RAD51 recruitment or stabilization at damage sites. The BCDX2 complex appears to act by facilitating the assembly or stability of the RAD51 nucleoprotein filament . The CX3 complex acts downstream of RAD51 recruitment to damage sites. Another complex, the BRCA1 - PALB2 - BRCA2 complex, cooperates with the RAD51 paralogs to load RAD51 onto ssDNA coated with RPA to form the essential recombination intermediate,
9387-403: Is still part of the definition of a gene in most textbooks. For example, The primary function of the genome is to produce RNA molecules. Selected portions of the DNA nucleotide sequence are copied into a corresponding RNA nucleotide sequence, which either encodes a protein (if it is an mRNA) or forms a 'structural' RNA, such as a transfer RNA (tRNA) or ribosomal RNA (rRNA) molecule. Each region of
9536-399: Is stored on the histones, as well as chemical modifications of the histone itself, regulate whether a particular region of DNA is accessible for gene expression . In addition to genes, eukaryotic chromosomes contain sequences involved in ensuring that the DNA is copied without degradation of end regions and sorted into daughter cells during cell division: replication origins , telomeres , and
9685-565: Is the mechanism by which several chemotherapeutic drugs act in order to disrupt DNA and cause cell death . Therefore, if the gene encoding MGMT in cancer cells is hypermethylated and in effect silenced or repressed, the chemotherapeutic drugs that act by methylating guanine will be more effective than in cancer cells that have a functional MGMT enzyme. Epigenetic biomarkers can also be utilized as tools for molecular prognosis. In primary tumor and mediastinal lymph node biopsy samples, hypermethylation of both CDKN2A and CDH13 serves as
9834-523: Is the second leading cause of cancer-caused fatalities in men, and within a man's lifetime, one in six men will have the disease. Alterations in histone acetylation and DNA methylation occur in various genes influencing prostate cancer, and have been seen in genes involved in hormonal response. More than 90% of prostate cancers show gene silencing by CpG island hypermethylation of the GSTP1 gene promoter , which protects prostate cells from genomic damage that
9983-631: Is the second most common type of cancer and leading cause of death in men and women in the United States, it is estimated that there is about 216,000 new cases and 160,000 deaths due to lung cancer. Initiation and progression of lung carcinoma is the result of the interaction between genetic, epigenetic and environmental factors. Most cases of lung cancer are because of genetic mutations in EGFR , KRAS , STK11 (also known as LKB1 ), TP53 (also known as p53 ), and CDKN2A (also known as p16 or INK4a ) with
10132-427: Is the study of epigenetic modifications to the DNA of cancer cells that do not involve a change in the nucleotide sequence, but instead involve a change in the way the genetic code is expressed. Epigenetic mechanisms are necessary to maintain normal sequences of tissue specific gene expression and are crucial for normal development. They may be just as important, if not even more important, than genetic mutations in
10281-511: Is thought to arise from increased RAD51 expression that can drive excess recombination. Under-expression of miR-506 is associated with both faster cancer recurrence and reduced survival in epithelial ovarian cancer patients. Methylation of the promoter of miR-34a, which leads to miR-34a under-expression, is observed in 79% of prostate cancers and 63% of primary melanomas . Reduced miR-34a expression has also been observed in 63% of non-small cell lung cancers , and 36% of colon cancers , and
10430-403: Is toxicoepigenetics. In this field, there is growing interest in mapping changes in histone modifications and their possible consequences. DNA damage , caused by UV light, ionizing radiation , environmental toxins, and metabolic chemicals, can also lead to genomic instability and cancer. The DNA damage response to double strand DNA breaks (DSB) is mediated in part by histone modifications. At
10579-406: The BRCA1 gene, 82% of aggressive breast cancers have low BRCA1 protein expression, and most of these reductions were due to chromatin remodeling by high levels of HMGA1 protein. HMGA2 protein specifically targets the promoter of ERCC1 , thus reducing expression of this DNA repair gene. ERCC1 protein expression was deficient in 100% of 47 evaluated colon cancers (though the extent to which HGMA2
10728-446: The MGMT promoter region (an epigenetic alteration). Similarly, out of 119 cases of mismatch repair-deficient colorectal cancers that lacked DNA repair gene PMS2 expression, PMS2 protein was deficient in 6 due to mutations in the PMS2 gene, while in 103 cases PMS2 expression was deficient because its pairing partner MLH1 was repressed due to promoter methylation (PMS2 protein is unstable in
10877-517: The MLH1 -deficiencies in sporadic colon cancers appeared to be due to over-expression of the microRNA miR-155 , which represses MLH1 expression. However, the majority of 68 sporadic colon cancers with reduced expression of the DNA mismatch repair protein MLH1 were found to be deficient due to epigenetic methylation of the CpG island of the MLH1 gene. In 28% of glioblastomas, the MGMT DNA repair protein
11026-511: The aging process. The centromere is required for binding spindle fibres to separate sister chromatids into daughter cells during cell division . Prokaryotes ( bacteria and archaea ) typically store their genomes on a single, large, circular chromosome . Similarly, some eukaryotic organelles contain a remnant circular chromosome with a small number of genes. Prokaryotes sometimes supplement their chromosome with additional small circles of DNA called plasmids , which usually encode only
11175-551: The bacterial RecA , Archaeal RadA , and yeast Rad51. The protein is highly conserved in most eukaryotes, from yeast to humans. The name RAD51 derives from RADiation sensitive protein 51. Two alternatively spliced transcript variants of this gene have been reported, which encode distinct proteins. Transcript variants utilizing alternative polyA signals also exist. In mammals , seven recA -like genes have been identified: Rad51, Rad51L1/B , Rad51L2/C , Rad51L3/D , XRCC2 , XRCC3 , and DMC1/Lim15 . All of these proteins, with
11324-401: The central dogma of molecular biology , which states that proteins are translated from RNA , which is transcribed from DNA . This dogma has since been shown to have exceptions, such as reverse transcription in retroviruses . The modern study of genetics at the level of DNA is known as molecular genetics . In 1972, Walter Fiers and his team were the first to determine the sequence of
11473-419: The centromere . Replication origins are the sequence regions where DNA replication is initiated to make two copies of the chromosome. Telomeres are long stretches of repetitive sequences that cap the ends of the linear chromosomes and prevent degradation of coding and regulatory regions during DNA replication . The length of the telomeres decreases each time the genome is replicated and has been implicated in
11622-460: The microhomology-mediated end joining (MMEJ) pathway and are up-regulated in cancer. MMEJ is an additional error-prone inaccurate repair pathway for double-strand breaks. In MMEJ repair of a double-strand break, an homology of 5-25 complementary base pairs between both paired strands is sufficient to align the strands, but mismatched ends (flaps) are usually present. MMEJ removes the extra nucleotides (flaps) where strands are joined, and then ligates
11771-549: The modern synthesis , a term introduced by Julian Huxley . This view of evolution was emphasized by George C. Williams ' gene-centric view of evolution . He proposed that the Mendelian gene is a unit of natural selection with the definition: "that which segregates and recombines with appreciable frequency." Related ideas emphasizing the centrality of Mendelian genes and the importance of natural selection in evolution were popularized by Richard Dawkins . The development of
11920-475: The neutral theory of evolution in the late 1960s led to the recognition that random genetic drift is a major player in evolution and that neutral theory should be the null hypothesis of molecular evolution. This led to the construction of phylogenetic trees and the development of the molecular clock , which is the basis of all dating techniques using DNA sequences. These techniques are not confined to molecular gene sequences but can be used on all DNA segments in
12069-750: The operon ; when the repressor is inactive transcription of the operon can occur (see e.g. Lac operon ). The products of operon genes typically have related functions and are involved in the same regulatory network . Though many genes have simple structures, as with much of biology, others can be quite complex or represent unusual edge-cases. Eukaryotic genes often have introns that are much larger than their exons, and those introns can even have other genes nested inside them . Associated enhancers may be many kilobase away, or even on entirely different chromosomes operating via physical contact between two chromosomes. A single gene can encode multiple different functional products by alternative splicing , and conversely
12218-508: The phenotype of the individual. Most biological traits occur under the combined influence of polygenes (a set of different genes) and gene–environment interactions . Some genetic traits are instantly visible, such as eye color or the number of limbs, others are not, such as blood type , the risk for specific diseases, or the thousands of basic biochemical processes that constitute life . A gene can acquire mutations in its sequence , leading to different variants, known as alleles , in
12367-449: The population . These alleles encode slightly different versions of a gene, which may cause different phenotypical traits. Genes evolve due to natural selection or survival of the fittest and genetic drift of the alleles. There are many different ways to use the term "gene" based on different aspects of their inheritance, selection, biological function, or molecular structure but most of these definitions fall into two categories,
12516-574: The 5'-to-3' strand at the DSB to generate a 3' single-strand DNA (ssDNA) overhang. In vertebrates, a number of RAD51 paralogs (see Figure) are essential for RAD51 protein recruitment or stabilization at sites of DNA damage. In vertebrates and plants, five paralogs of RAD51 are expressed in somatic cells, including RAD51B ( RAD51L1 ), RAD51C (RAD51L2), RAD51D ( RAD51L3 ), XRCC2 and XRCC3 . They each share about 25% amino acid sequence identity with RAD51 and with each other. Outside of plants and vertebrates,
12665-820: The BMI1 component of the PRC1 complex is deregulated in chondrosarcoma, Ewing's sarcoma, and osteosarcoma, and expression of the EZH2 component of the PRC2 complex is altered in Ewing's sarcoma and rhabdomyosarcoma. Similarly, expression of another epigenetic modifier, the LSD1 histone demethylase, is increased in chondrosarcoma, Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma. Drug targeting and inhibition of EZH2 in Ewing's sarcoma, or of LSD1 in several sarcomas, inhibits tumor cell growth in these sarcomas. Lung cancer
12814-473: The CpG island shores move into CpG islands, or hypomethylation of CpG islands move into CpG island shores eliminating sharp epigenetic boundaries between these genetic elements. In cancer cells "global hypomethylation" due to disruption in DNA methyltransferases (DNMTs) may promote mitotic recombination and chromosome rearrangement , ultimately resulting in aneuploidy when the chromosomes fail to separate properly during mitosis . CpG island methylation
12963-404: The DNA helix that produces a functional RNA molecule constitutes a gene. We define a gene as a DNA sequence that is transcribed. This definition includes genes that do not encode proteins (not all transcripts are messenger RNA). The definition normally excludes regions of the genome that control transcription but are not themselves transcribed. We will encounter some exceptions to our definition of
13112-450: The DNA sequence is used as a template for the production of an RNA molecule or a protein that performs some function. The emphasis on function is essential because there are stretches of DNA that produce non-functional transcripts and they do not qualify as genes. These include obvious examples such as transcribed pseudogenes as well as less obvious examples such as junk RNA produced as noise due to transcription errors. In order to qualify as
13261-766: The DNA to loop so that the regulatory sequence (and bound transcription factor) become close to the RNA polymerase binding site. For example, enhancers increase transcription by binding an activator protein which then helps to recruit the RNA polymerase to the promoter; conversely silencers bind repressor proteins and make the DNA less available for RNA polymerase. The mature messenger RNA produced from protein-coding genes contains untranslated regions at both ends which contain binding sites for ribosomes , RNA-binding proteins , miRNA , as well as terminator , and start and stop codons . In addition, most eukaryotic open reading frames contain untranslated introns , which are removed and exons , which are connected together in
13410-506: The Mendelian gene or the molecular gene. The Mendelian gene is the classical gene of genetics and it refers to any heritable trait. This is the gene described in The Selfish Gene . More thorough discussions of this version of a gene can be found in the articles Genetics and Gene-centered view of evolution . The molecular gene definition is more commonly used across biochemistry, molecular biology, and most of genetics —
13559-565: The RAD51-ssDNA filament. In mice and humans, the BRCA2 complex primarily mediates orderly assembly of RAD51 on ssDNA, which is an active substrate in homologous pairing and strand invasion. BRCA2 also redirects RAD51 from dsDNA and prevents its dissociation from ssDNA. However, in the presence of a BRCA2 mutation, human RAD52 can mediate RAD51 assembly on ssDNA and substitute for BRCA2 in homologous recombinational DNA repair, though with lower efficiency than BRCA2. Further steps are detailed in
13708-856: The Misplaced Pages articles on RAD51 and BRCA2 , such cancers ordinarily have epigenetic deficiencies in other DNA repair genes. These repair deficiencies would likely cause increased unrepaired DNA damages. The over-expression of RAD51 and BRCA2 seen in these cancers may reflect selective pressures for compensatory RAD51 or BRCA2 over-expression and increased homologous recombinational repair to at least partially deal with such excess DNA damages. In those cases where RAD51 or BRCA2 are under-expressed, this would itself lead to increased unrepaired DNA damages. Replication errors past these damages (see translesion synthesis ) could cause increased mutations and cancer, so that under-expression of RAD51 or BRCA2 would be carcinogenic in itself. Cyan-highlighted genes are in
13857-400: The absence of MLH1). In the other 10 cases, loss of PMS2 expression was likely due to epigenetic overexpression of the microRNA, miR-155, which down-regulates MLH1. Epigenetic defects in DNA repair genes are frequent in cancers. In the table, multiple cancers were evaluated for reduced or absent expression of the DNA repair gene of interest, and the frequency shown is the frequency with which
14006-433: The adenines of one strand are paired with the thymines of the other strand, and so on. Due to the chemical composition of the pentose residues of the bases, DNA strands have directionality. One end of a DNA polymer contains an exposed hydroxyl group on the deoxyribose ; this is known as the 3' end of the molecule. The other end contains an exposed phosphate group; this is the 5' end . The two strands of
14155-556: The adjacent Rad51 filaments suggesting that cross-talk between these two recombinases may affect their biochemical properties. In aged and chemotherapy treated females, oocytes and follicles are depleted by apoptosis (programmed cell death) leading to ovarian failure. DNA damage-induced oocyte apoptosis depends on the efficiency of the DNA repair machinery that in turn declines with age. Survival of oocytes following chemotherapy or aging can be enhanced by increased expression of Rad51. The Rad51-induced oocyte resistance to apoptosis
14304-486: The article Homologous recombination . Rad51 has a crucial function in meiotic prophase in mice, with Rad51 knockout leading to a depletion of late prophase I spermatocytes . During meiosis , the two recombinases, Rad51 and Dmc1 , interact with single-stranded DNA to form specialized filaments that are adapted for facilitating recombination between homologous chromosomes . Both Rad51 and Dmc1 have an intrinsic ability to self-aggregate. The presence of Dmc1 stabilizes
14453-668: The biosynthetic demands of cancer cells, metabolic pathways are altered by manipulating oncogenes and tumor suppressive genes concurrently. The accumulation of certain metabolites in cancer can target epigenetic enzymes to globally alter the epigenetic landscape. Cancer-related metabolic changes lead to locus-specific recoding of epigenetic marks. Cancer epigenetics can be precisely reprogramed by cellular metabolism through 1) dose-responsive modulation of cancer epigenetics by metabolites; 2) sequence-specific recruitment of metabolic enzymes; and 3) targeting of epigenetic enzymes by nutritional signals. In addition to modulating metabolic programming on
14602-574: The cancers had an epigenetic deficiency of gene expression. Such epigenetic deficiencies likely arise early in carcinogenesis , since they are also frequently found (though at somewhat lower frequency) in the field defect surrounding the cancer from which the cancer likely arose (see Table). It appears that cancers may frequently be initiated by an epigenetic reduction in expression of one or more DNA repair enzymes. Reduced DNA repair likely allows accumulation of DNA damages. Error prone translesion synthesis past some of these DNA damages may give rise to
14751-517: The carcinogenesis of this tumor type. Fanconi anemia (FA) is a hereditary condition characterized by cellular hypersensitivity to DNA cross-linking agents. A dominant negative mutation in the Rad51 gene has been reported to give rise to an FA-like phenotype with features of mental retardation. This report included evidence that Rad51-mediated homologous recombinational repair likely has an important role in neurodevelopment. RAD51 has been shown to interact with: Gene In biology ,
14900-741: The causes of leukemia. There are about 15,000 new cases of sarcoma in the US each year, and about 6,200 people were projected to die of sarcoma in the US in 2014. Sarcomas comprise a large number of rare, histogenetically heterogeneous mesenchymal tumors that, for example, include chondrosarcoma, Ewing's sarcoma, leiomyosarcoma, liposarcoma, osteosarcoma, synovial sarcoma, and (alveolar and embryonal) rhabdomyosarcoma. Several oncogenes and tumor suppressor genes are epigenetically altered in sarcomas. These include APC, CDKN1A, CDKN2A, CDKN2B, Ezrin, FGFR1, GADD45A, MGMT, STK3, STK4, PTEN, RASSF1A, WIF1, as well as several miRNAs. Expression of epigenetic modifiers such as that of
15049-524: The changing epigenetic profiles of cancerous cells. The histone variants of the H2A family are highly conserved in mammals, playing critical roles in regulating many nuclear processes by altering chromatin structure. One of the key H2A variants, H2A.X, marks DNA damage, facilitating the recruitment of DNA repair proteins to restore genomic integrity. Another variant, H2A.Z, plays an important role in both gene activation and repression. A high level of H2A.Z expression
15198-481: The coding regions are epigenetically silenced in cancer due to histone deacetylase activity. When these microRNAs are expressed at a low level, then HMGA1 and HMGA2 proteins are expressed at a high level. HMGA1 and HMGA2 target (reduce expression of) BRCA1 and ERCC1 DNA repair genes. Thus DNA repair can be reduced, likely contributing to cancer progression. The chart in this section shows some frequent DNA damaging agents, examples of DNA lesions they cause, and
15347-402: The complexity of these diverse phenomena, where a gene is defined as a union of genomic sequences encoding a coherent set of potentially overlapping functional products. This definition categorizes genes by their functional products (proteins or RNA) rather than their specific DNA loci, with regulatory elements classified as gene-associated regions. The existence of discrete inheritable units
15496-463: The correct regulatory regions in leukemia associated translocations or insertions causing malignant transformation controlled by HOX genes. This is what leads to the increase in white blood cells. Leukemia related genes are managed by the same pathways that control epigenetics, signaling transduction, transcriptional regulation, and energy metabolism. It was indicated that infections, electromagnetic fields and increased birth weight can contribute to being
15645-456: The damaged region (see homologous recombination models ). Numerous studies report that RAD51 is over-expressed in different cancers (see Table 1). In many of these studies, elevated expression of RAD51 is correlated with decreased patient survival. However, there are also some reports of under-expression of RAD51 in cancers (see Table 1). Where RAD51 expression was quantified in conjunction with BRCA1 expression, an inverse correlation
15794-450: The different epigenomic profiles to determine the stage of development or level of aggressiveness of a particular cancer in patients. For example, hypermethylation of the genes coding for Death-Associated Protein Kinase (DAPK), p16, and Epithelial Membrane Protein 3 (EMP3) have been linked to more aggressive forms of lung , colorectal , and brain cancers . This type of knowledge can affect
15943-422: The direct route from infection to cancer is sometimes detoured to a precancerous state in cervix intraepithelial neoplasia. Additionally, increased CpG site methylation was found in low levels in most of the five host nuclear genes studied, including 5/5 TERT , 1/4 DAPK1 , 2/5 RARB , MAL , and CADM1 . Furthermore, 1/3 of CpG sites in mitochondrial DNA were associated with increased methylation in CIN3+. Thus,
16092-524: The distinction between a heterozygote and homozygote , and the phenomenon of discontinuous inheritance. Prior to Mendel's work, the dominant theory of heredity was one of blending inheritance , which suggested that each parent contributed fluids to the fertilization process and that the traits of the parents blended and mixed to produce the offspring. Charles Darwin developed a theory of inheritance he termed pangenesis , from Greek pan ("all, whole") and genesis ("birth") / genos ("origin"). Darwin used
16241-597: The drop in methylation of the gene's CpG island (an event that normally activates genes). Some research has focused on blocking the action of BRD4 on acetylated histones, which has been shown to increase the expression of the Myc protein, implicated in several cancers. The development process of the drug to bind to BRD4 is noteworthy for the collaborative, open approach the team is taking. The tumor suppressor gene p53 regulates DNA repair and can induce apoptosis in dysregulated cells. E Soto-Reyes and F Recillas-Targa elucidated
16390-410: The early 1950s the prevailing view was that the genes in a chromosome acted like discrete entities arranged like beads on a string. The experiments of Benzer using mutants defective in the rII region of bacteriophage T4 (1955–1959) showed that individual genes have a simple linear structure and are likely to be equivalent to a linear section of DNA. Collectively, this body of research established
16539-460: The epimutation of the DNA repair gene and the mutation with the selective advantage, further DNA damages will accumulate, and these could, in turn, give rise to further mutations with still greater selective advantages. Epigenetic defects in DNA repair may thus contribute to the characteristic high frequency of mutations in the genomes of cancers, and cause their carcinogenic progression. Cancers have high levels of genome instability , associated with
16688-495: The exception of meiosis-specific DMC1, are essential for development in mammals. Rad51 is a member of the RecA-like NTPases . In humans, RAD51 is a 339- amino acid protein that plays a major role in homologous recombination of DNA during double strand break repair. In this repair process, an ATP-dependent DNA strand exchange takes place in which a template strand invades base-paired strands of homologous DNA molecules. RAD51
16837-434: The excess of DNA damage. Under-expression of RAD51 would lead to increases in unrepaired DNA damage. When these DNA lesions are unrepaired, replication errors can occur near to the damaged sites (see translesion synthesis ), leading to increased mutations and cancer. Double-strand break (DSB) repair by homologous recombination is initiated by 5' to 3' strand resection ( DSB resection ). In humans, DNA2 nuclease resects
16986-514: The fact that both protein-coding genes and noncoding genes have been known for more than 50 years, there are still a number of textbooks, websites, and scientific publications that define a gene as a DNA sequence that specifies a protein. In other words, the definition is restricted to protein-coding genes. Here is an example from a recent article in American Scientist. ... to truly assess the potential significance of de novo genes, we relied on
17135-508: The fetus by epigenetic mechanisms. While epigenetic effects may preserve the effect of a teratogen such as diethylstilbestrol throughout the life of an affected child, the possibility of birth defects resulting from exposure of fathers or in second and succeeding generations of offspring has generally been rejected on theoretical grounds and for lack of evidence. However, a range of male-mediated abnormalities have been demonstrated, and more are likely to exist. FDA label information for Vidaza,
17284-413: The functional product. The discovery of introns in the 1970s meant that many eukaryotic genes were much larger than the size of the functional product would imply. Typical mammalian protein-coding genes, for example, are about 62,000 base pairs in length (transcribed region) and since there are about 20,000 of them they occupy about 35–40% of the mammalian genome (including the human genome). In spite of
17433-630: The gene that is described in terms of DNA sequence. There are many different definitions of this gene — some of which are misleading or incorrect. Very early work in the field that became molecular genetics suggested the concept that one gene makes one protein (originally 'one gene - one enzyme'). However, genes that produce repressor RNAs were proposed in the 1950s and by the 1960s, textbooks were using molecular gene definitions that included those that specified functional RNA molecules such as ribosomal RNA and tRNA (noncoding genes) as well as protein-coding genes. This idea of two kinds of genes
17582-903: The genes highlighted by red, gray or cyan describe the epigenetic alteration(s) and the cancer(s) in which these epimutations are found. Two broad experimental survey articles also document most of these epigenetic DNA repair deficiencies in cancers. Red-highlighted genes are frequently reduced or silenced by epigenetic mechanisms in various cancers. When these genes have low or absent expression, DNA damages can accumulate. Replication errors past these damages (see translesion synthesis ) can lead to increased mutations and, ultimately, cancer. Epigenetic repression of DNA repair genes in accurate DNA repair pathways appear to be central to carcinogenesis . The two gray-highlighted genes RAD51 and BRCA2 , are required for homologous recombinational repair. They are sometimes epigenetically over-expressed and sometimes under-expressed in certain cancers. As indicated in
17731-503: The genome of a healthy cell. In fact, cancer cell genomes have 20-50% less methylation at individual CpG dinucleotides across the genome. CpG islands found in promoter regions are usually protected from DNA methylation. In cancer cells CpG islands are hypomethylated The regions flanking CpG islands called CpG island shores are where most DNA methylation occurs in the CpG dinucleotide context. Cancer cells are deferentially methylated at CpG island shores. In cancer cells, hypermethylation in
17880-421: The genome. The vast majority of organisms encode their genes in long strands of DNA (deoxyribonucleic acid). DNA consists of a chain made from four types of nucleotide subunits, each composed of: a five-carbon sugar ( 2-deoxyribose ), a phosphate group, and one of the four bases adenine , cytosine , guanine , and thymine . Two chains of DNA twist around each other to form a DNA double helix with
18029-421: The genomes of complex multicellular organisms , including humans, contain an absolute majority of DNA without an identified function. This DNA has often been referred to as " junk DNA ". However, more recent analyses suggest that, although protein-coding DNA makes up barely 2% of the human genome , about 80% of the bases in the genome may be expressed, so the term "junk DNA" may be a misnomer. The structure of
18178-561: The importance of the CTCF protein in regulating p53 expression. CTCF, or CCCTC binding factor, is a zinc finger protein that insulates the p53 promoter from accumulating repressive histone marks. In certain types of cancer cells, the CTCF protein does not bind normally, and the p53 promoter accumulates repressive histone marks, causing p53 expression to decrease. Mutations in the epigenetic machinery itself may occur as well, potentially responsible for
18327-477: The intermediate template for the synthesis of a protein. The transmission of genes to an organism's offspring , is the basis of the inheritance of phenotypic traits from one generation to the next. These genes make up different DNA sequences, together called a genotype , that is specific to every given individual, within the gene pool of the population of a given species . The genotype, along with environmental and developmental factors, ultimately determines
18476-835: The miRNAs indicated in parentheses: ATM (miR-421), RAD52 (miR-210, miR-373), RAD23B (miR-373), MSH2 (miR-21), BRCA1 (miR-182) and P53 (miR-504, miR-125b). More recently, Tessitore et al. listed further DNA repair genes that are directly targeted by additional miRNAs, including ATM (miR-18a, miR-101), DNA-PK (miR-101), ATR (miR-185), Wip1 (miR-16), MLH1, MSH2 and MSH6 (miR-155), ERCC3 and ERCC4 (miR-192) and UNG2 (mir-16, miR-34c and miR-199a). Of these miRNAs, miR-16, miR-18a, miR-21, miR-34c, miR-125b, miR-101, miR-155, miR-182, miR-185 and miR-192 are among those identified by Schnekenburger and Diederich as over-expressed in colon cancer through epigenetic hypomethylation. Over expression of any one of these miRNAs can cause reduced expression of its target DNA repair gene. Up to 15% of
18625-403: The most common type of lung cancer being an inactivation at p16. p16 is a tumor suppressor protein that occurs in mostly in humans the functional significance of the mutations was tested on many other species including mice, cats, dogs, monkeys and cows the identification of these multiple nonoverlapping clones was not entirely surprising since the reduced stringency hybridization of a zoo blot with
18774-780: The mutation frequency in the whole genome between generations for humans (parent to child) is about 70 new mutations per generation. In the protein coding regions of the genome, there are only about 0.35 mutations between parent/child generations (less than one mutated protein per generation). Whole genome sequencing in blood cells for a pair of identical twin 100-year-old centenarians only found 8 somatic differences, though somatic variation occurring in less than 20% of blood cells would be undetected. While DNA damages may give rise to mutations through error prone translesion synthesis , DNA damages can also give rise to epigenetic alterations during faulty DNA repair processes. The DNA damages that accumulate due to epigenetic DNA repair defects can be
18923-512: The nucleosome. Certain histone modifying enzymes can add or remove functional groups to the histones, and these modifications influence the level of transcription of the genes wrapped around those histones and the level of DNA replication. Histone modification profiles of healthy and cancerous cells tend to differ. In comparison to healthy cells, cancerous cells exhibit decreased monoacetylated and trimethylated forms of histone H4 (decreased H4ac and H4me3). Additionally, mouse models have shown that
19072-546: The nucleotide base, creating pyrimidine dimers . When mutation results in loss of heterozygosity at tumor suppressor gene sites, these genes may become inactive. Single base pair mutations during replication can also have detrimental effects. Eukaryotic DNA has a complex structure. It is generally wrapped around special proteins called histones to form a structure called a nucleosome . A nucleosome consists of 2 sets of 4 histones: H2A , H2B , H3 , and H4 . Additionally, histone H1 contributes to DNA packaging outside of
19221-413: The nucleus. Splicing, followed by CPA, generate the final mature mRNA , which encodes the protein or RNA product. Many noncoding genes in eukaryotes have different transcription termination mechanisms and they do not have poly(A) tails. Many prokaryotic genes are organized into operons , with multiple protein-coding sequences that are transcribed as a unit. The genes in an operon are transcribed as
19370-500: The pathways that deal with these DNA damages. At least 169 enzymes are either directly employed in DNA repair or influence DNA repair processes. Of these, 83 are directly employed in repairing the 5 types of DNA damages illustrated in the chart. Some of the more well studied genes central to these repair processes are shown in the chart. The gene designations shown in red, gray or cyan indicate genes frequently epigenetically altered in various types of cancers. Misplaced Pages articles on each of
19519-431: The phosphate–sugar backbone spiralling around the outside, and the bases pointing inward with adenine base pairing to thymine and guanine to cytosine. The specificity of base pairing occurs because adenine and thymine align to form two hydrogen bonds , whereas cytosine and guanine form three hydrogen bonds. The two strands in a double helix must, therefore, be complementary , with their sequence of bases matching such that
19668-578: The promoters of genes in the tumors while these CpG islands are not methylated in the adjacent mucosa. Manipulation of epigenetic alterations holds great promise for cancer prevention, detection, and therapy. In different types of cancer, a variety of epigenetic mechanisms can be perturbed, such as the silencing of tumor suppressor genes and activation of oncogenes by altered CpG island methylation patterns, histone modifications, and dysregulation of DNA binding proteins . There are several medications which have epigenetic impact, that are now used in
19817-448: The same probe also revealed 10-15 positive EcoRI fragments in all species tested. Previously, epigenetic profiles were limited to individual genes under scrutiny by a particular research team. Recently, however, scientists have been moving toward a more genomic approach to determine an entire genomic profile for cancerous versus healthy cells. Popular approaches for measuring CpG methylation in cells include: Since bisulfite sequencing
19966-467: The strand of DNA like a train on a monorail, transcribing it into its messenger RNA form. This point brings us to our second important criterion: A true gene is one that is both transcribed and translated. That is, a true gene is first used as a template to make transient messenger RNA, which is then translated into a protein. This restricted definition is so common that it has spawned many recent articles that criticize this "standard definition" and call for
20115-473: The strands to create an intact DNA double helix. MMEJ almost always involves at least a small deletion, so that it is a mutagenic pathway. FEN1 , the flap endonuclease in MMEJ, is epigenetically increased by promoter hypomethylation and is over-expressed in the majority of cancers of the breast, prostate, stomach, neuroblastomas, pancreas, and lung. PARP1 is also over-expressed when its promoter region ETS site
20264-461: The sugar ribose rather than deoxyribose . RNA also contains the base uracil in place of thymine . RNA molecules are less stable than DNA and are typically single-stranded. Genes that encode proteins are composed of a series of three- nucleotide sequences called codons , which serve as the "words" in the genetic "language". The genetic code specifies the correspondence during protein translation between codons and amino acids . The genetic code
20413-805: The term gemmule to describe hypothetical particles that would mix during reproduction. Mendel's work went largely unnoticed after its first publication in 1866, but was rediscovered in the late 19th century by Hugo de Vries , Carl Correns , and Erich von Tschermak , who (claimed to have) reached similar conclusions in their own research. Specifically, in 1889, Hugo de Vries published his book Intracellular Pangenesis , in which he postulated that different characters have individual hereditary carriers and that inheritance of specific traits in organisms comes in particles. De Vries called these units "pangenes" ( Pangens in German), after Darwin's 1868 pangenesis theory. Twenty years later, in 1909, Wilhelm Johannsen introduced
20562-436: The term gene , he explained his results in terms of discrete inherited units that give rise to observable physical characteristics. This description prefigured Wilhelm Johannsen 's distinction between genotype (the genetic material of an organism) and phenotype (the observable traits of that organism). Mendel was also the first to demonstrate independent assortment , the distinction between dominant and recessive traits,
20711-412: The term "gene" (inspired by the ancient Greek : γόνος, gonos , meaning offspring and procreation) and, in 1906, William Bateson , that of " genetics " while Eduard Strasburger , among others, still used the term "pangene" for the fundamental physical and functional unit of heredity. Advances in understanding genes and inheritance continued throughout the 20th century. Deoxyribonucleic acid (DNA)
20860-413: The total fragment terminating when it reaches about 2 μm in length. However, disassociation of Rad51 from dsDNA is slow and incomplete, suggesting that there is a separate mechanism that accomplishes this. In eukaryotes, the RAD51 protein has a central role in homologous recombinational repair, where it catalyses strand transfer between a broken sequence and its undamaged homologue, enabling re-synthesis of
21009-482: The transcription start site was observed. Loss of CTCF binding and an increase in repressive histone marks, H3K9me3 and H3K27me3, correlates with DNA methylation and miR-125b1 silencing. Mechanistically, CTCF may function as a boundary element to stop the spread of DNA methylation. Results from experiments conducted by Soto-Reyes et al. indicate a negative effect of methylation on the function and expression of miR-125b1. Therefore, they concluded that DNA methylation has
21158-420: The way that doctors will diagnose and choose to treat their patients. Another factor that will influence the treatment of patients is knowing how well they will respond to certain treatments. Personalized epigenomic profiles of cancerous cells can provide insight into this field. For example, MGMT is an enzyme that reverses the addition of alkyl groups to the nucleotide guanine . Alkylating guanine, however,
21307-424: The word gene has two meanings. The Mendelian gene is a basic unit of heredity . The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA . There are two types of molecular genes: protein-coding genes and non-coding genes. During gene expression (the synthesis of RNA or protein from a gene), DNA is first copied into RNA . RNA can be directly functional or be
21456-446: Was first suggested by Gregor Mendel (1822–1884). From 1857 to 1864, in Brno , Austrian Empire (today's Czech Republic), he studied inheritance patterns in 8000 common edible pea plants , tracking distinct traits from parent to offspring. He described these mathematically as 2 combinations where n is the number of differing characteristics in the original peas. Although he did not use
21605-771: Was found. This has been interpreted as selection, given that increased RAD51 expression and thus increased homologous recombinational repair (HRR) (by the HRR RAD52-RAD51 back-up pathway) may compensate for the accumulation of DNA damage arising from deficient BRCA1 . Furthermore, many cancers have epigenetic deficiencies in various DNA repair genes (see Frequencies of epimutations in DNA repair genes in cancers ) that can suppress their expression, likely leading to increases in unrepaired DNA damage. RAD51 overexpression seen in many cancers may therefore be compensatory (as seen in BRCA1 deficiency), resulting in increased HRR that may enable cancer cell survival by partially ameliorating
21754-399: Was generally associated with decreased HR and increased sensitivity of the cells to DNA damaging agents. This protein is also found to interact with PALB2 and BRCA2 , which may be important for the cellular response to DNA damage. BRCA2 is shown to regulate both the intracellular localization and DNA-binding ability of this protein. Loss of these controls following BRCA2 inactivation may be
21903-566: Was involved is unknown). Palmieri et al. showed that each of the miRNAs that target HMGA genes are drastically reduced in almost all human pituitary adenomas studied, when compared with the normal pituitary gland. Consistent with the down-regulation of these HMGA-targeting miRNAs, an increase in the HMGA1 and HMGA2-specific mRNAs was observed. Three of these microRNAs (miR-16, miR-196a and Let-7a) have methylated promoters and therefore low expression in colon cancer. For two of these, miR-15 and miR-16,
22052-729: Was reported to coincide with RAD51 repression. Further study demonstrated that transfecting breast cancer cells with a vector over-expressing miR-155 represses RAD51 expression, resulting in decreased homologous recombination and increased sensitivity to ionizing radiation. Four further miRNAs that repress RAD51 (miR-148b* and miR-193b*, miR-506, and miR-34a) are under-expressed in cancers, presumably leading to induction of RAD51 expression, with under-expression of miR-148b and miR-193b causing an observed induction of RAD51 expression. Furthermore, deletions of miR-148b* and miR-193b* in serous ovarian tumors correlates with increased losses of heterozygosity (LOH), which may be carcinogenic. This
22201-430: Was shown to be the molecular repository of genetic information by experiments in the 1940s to 1950s. The structure of DNA was studied by Rosalind Franklin and Maurice Wilkins using X-ray crystallography , which led James D. Watson and Francis Crick to publish a model of the double-stranded DNA molecule whose paired nucleotide bases indicated a compelling hypothesis for the mechanism of genetic replication. In
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