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147-450: 4GGA , 4GGC , 4GGD , 4N14 , 5G04 991 107995 ENSG00000117399 ENSMUSG00000006398 Q12834 Q9JJ66 NM_001255 NM_023223 NP_001246 NP_075712 The cell division cycle protein 20 homolog is an essential regulator of cell division that is encoded by the CDC20 gene in humans. To the best of current knowledge its most important function is to activate

294-584: 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

441-518: 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. Spindle assembly checkpoint The beginning of metaphase

588-477: A MAD1-C-MAD2-p31 complex and releases the p31 through unknown mechanisms. The resulting MAD1-C-MAD2 complex recruits the open conformer of Mad2 (O-Mad2) to the kinetochores. This O-Mad2 changes its conformation to closed Mad2 (C-Mad2) and binds Mad1. This Mad1/C-Mad2 complex is responsible for the recruitment of more O-Mad2 to the kinetochores, which changes its conformation to C-Mad2 and binds Cdc20 in an auto-amplification reaction. Since MAD1 and CDC20 both contain

735-534: A balanced way. During S phase, the centrosome starts to duplicate. Just at the beginning of mitosis, both centrioles achieve their maximal length, recruit additional material and their capacity to nucleate microtubules increases. As mitosis progresses, both centrosomes separate to generate the mitotic spindle. In this way, the mitotic spindle has two poles emanating microtubules. Microtubules (MTs) are long proteic filaments, with asymmetric extremities: one end termed "minus" (-) end, relatively stable and close to

882-568: A closed form (C-Mad2.) The C-Mad2 bound to Mad1 then dimerizes with a second O-Mad2 and catalyzes its closure around Cdc20. This C-Mad2 and Cdc20 complex, the MCC, leaves Mad1 and C-Mad2 at the kinetochore to form another MCC. The MCCs each sequester two Cdc20 molecules to prevent their interaction with the APC/C, thereby maintaining the SAC. Mps1's phosphorylation of Spc105 is both necessary and sufficient to initiate

1029-590: A complete set of chromatids. The mechanism responsible for the correct distribution of sister chromatids during cell division is named chromosome segregation . To ensure that chromosome segregation takes place correctly, cells have developed a precise and complex mechanism. In the first place, cells must coordinate centrosome duplication with DNA replication, and a failure in this coordination will generate monopolar or multipolar mitotic spindles, which generally will produce abnormal chromosome segregation, because in this case, chromosome distribution will not take place in

1176-483: A configuration named merotelic , which is not detected by the spindle checkpoint but that may generate lagging chromosomes during anaphase and, consequently, aneuploidy. Merotelic orientation (characterized by the absence of tension between sister kinetochores) is frequent at the beginning of mitosis, but the protein Aurora B (a kinase conserved from yeast to vertebrates) detects and eliminates this type of anchoring. (Aurora B

1323-445: 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

1470-495: 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

1617-488: 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

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1764-407: A functioning SAC. Furthermore, depletions of various SAC proteins have revealed that MAD2 and BUBR1 depletions affect the timing of mitosis independently of kinetochores, while depletions of other SAC proteins result in a dysfunctional SAC without altering the duration of mitosis. Thus it is possible that the SAC functions through a two-stage timer where MAD2 and BUBR1 control the duration of mitosis in

1911-434: 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

2058-565: 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

2205-410: 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

2352-404: 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

2499-565: 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

2646-439: 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

2793-448: A good target for further clinical development. Aurora B inhibitors, which are also in clinical development lead to abnormal kinetochore to microtubule attachment and abrogate the mitotic checkpoint as well. Survivin is also an attractive molecular target for clinical therapeutic development as it acts as a major node in a multitude of pathways, one of which is spindle formation and checkpoint control. Even further approaches have included

2940-452: A group of chromosomic ATPases highly conserved, and form an heterodimer (Smc1p/Smc3p). Scc1p is the homolog in S.cerevisiae of Rad21, first identified as a protein involved in DNA repair in S. pombe . These four proteins are essential in yeast, and a mutation in any of them will produce premature sister chromatid separation. In yeast, cohesin binds to preferential sites along chromosome arms, and

3087-611: A high incidence of tumorigenesis only when alterations in the levels of specific mitotic checkpoint components (either reduction or overexpression) in tissues is also inducing other defects able to predispose them to tumors. That is, defects such as an increase in DNA damage, chromosomal rearrangements, and/or a decreased incidence of cell death. For some mitotic checkpoint components, it is known that they are implicated in functions outside mitosis: nuclear import (Mad1), transcriptional repression (Bub3), and cell death, DNA damage response, aging, and megakaryopoiesis for BubR1. All this supports

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3234-448: 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

3381-462: A major effect on cell cycle checkpoint regulators and has been shown to act at the G1 checkpoint in the past, but now appears to be important in regulating the spindle checkpoint as well. Another key aspect of cancer is inhibition of cell death or apoptosis . Survivin , a member of the inhibitor of apoptosis (IAP) family, is localized in pools at microtubules of the mitotic spindle near the centrosomes and at

3528-572: 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

3675-521: A polyprotein complex as an essential player in sister chromatids cohesion (see the review from Hirano in 2000 ). This complex is known as the cohesin complex and in Saccharomyces cerevisiae is composed of at least four subunits: Smc1p, Smc3p, Scc1p (or Mcd1p) and Scc3p. Both Smc1p and Smc3p belong to the family of proteins for the Structural Maintenance of Chromosomes (SMC), which constitute

3822-400: 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

3969-438: A process termed DNA replication . Once DNA replication has finished, in eukaryotes the DNA molecule is compacted and condensed, to form the mitotic chromosomes , each one constituted by two sister chromatids , which stay held together by the establishment of cohesion between them; each chromatid is a complete DNA molecule, attached via microtubules to one of the two centrosomes of the dividing cell, located at opposed poles of

4116-419: 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

4263-412: A similar MAD2-binding motif, the empty O-MAD2 conformation changes to C-MAD2 while binding to CDC20. This positive feedback loop is negatively regulated by p31 , which competitively binds to C-MAD2 bound to either MAD1 or CDC20 and reduces further O-MAD2 binding to C-MAD2. Further control mechanisms may also exist, considering that p31 is not present in lower eukaryotes. The 'template model' nomenclature

4410-413: A similar amount is cut in anaphase, when it disappears from centromeres. On the other hand, some experiments show that sister chromatids cohesion in the arms is lost gradually after sister centromeres have separated, and sister chromatids move toward the opposite poles of the cell. According to some observations, a fraction of cohesins in the chromosomal arms and the centromeric cohesins are protected by

4557-412: 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

CDC20 - Misplaced Pages Continue

4704-472: 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

4851-409: 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

4998-477: Is a frequent event in cancer , it was initially thought that these genes could be mutated in cancerous tissues. In some cancers the genes that underlie the defects resulting in transformation are well characterized. In the hematological cancers such as multiple myeloma cytogenetic abnormalities are very common due to the inherent nature of DNA breaks needed for immunoglobulin gene rearrangement. However, defects in proteins such as MAD2 that function predominantly at

5145-676: Is about 499 amino acids long, and contains at least four phosphorylation sites near the N-terminus. In between these phosphorylation sites, which play regulatory roles, are the C-box, the KEN-box, the Mad2-interacting motif, and the Cry box. The KEN-box, as well as the Cry box, are important recognition and degradation sequences for the APC/C complex (see below). CDC20 has been shown to interact with: However,

5292-529: Is an active signal produced by improperly attached kinetochores , which is conserved in all eukaryotes . The SAC stops the cell cycle by negatively regulating CDC20, thereby preventing the activation of the polyubiquitynation activities of anaphase promoting complex (APC). The proteins responsible for the SAC signal compose the mitotic checkpoint complex (MCC), which includes SAC proteins, MAD2 / MAD3 (mitotic arrest deficient), BUB3 (budding uninhibited by benzimidazole), and CDC20 . Other proteins involved in

5439-442: Is an important target of the SAC, which consists of several different proteins, including Mad2, Mad3(BubR1), and Bub3. In fact, these three proteins, together with CDC20, likely form the mitotic checkpoint complex (MCC), which inhibits APC/C so that anaphase cannot begin prematurely. Moreover, Bub1 phosphorylates and thus inhibits CDC20 directly, while in yeast Mad2 and Mad3, when bound to CDC20, trigger its autoubiquitination. CDC20

5586-415: Is big enough or because they receive the appropriate stimulus, they activate the mechanism to enter into the cell cycle, and they duplicate most organelles during S (synthesis) phase, including their centrosome . Therefore, when the cell division process will end, each daughter cell will receive a complete set of organelles. At the same time, during S phase all cells must duplicate their DNA very precisely,

5733-456: 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,

5880-415: Is characterized by the connection of the microtubules to the kinetochores of the chromosomes, as well as the alignment of the chromosomes in the middle of the cell. Each chromatid has its own kinetochore, and all of the microtubules that are bound to kinetochores of sister chromatids radiate from opposite poles of the cell. These microtubules exert a pulling force on the chromosomes towards the opposite ends of

6027-542: Is composed of BUB3, which binds to Mad3 and BUB1B through the short linear motif known as the GLEBS motif. The exact order of attachments which must take place in order to form the MCC remains unknown. It is possible that Mad2-Cdc20 form a complex at the same time as BUBR1-BUB3-Cdc20 form another complex, and these two subcomplexes are consequently combined to form the mitotic checkpoint complex. In human cells, binding of BUBR1 to CDC20 requires prior binding of MAD2 to CDC20, so it

CDC20 - Misplaced Pages Continue

6174-511: Is frequently overexpressed in various types of tumors and currently is a target for the development of anticancer drugs. ) Sister chromatids stay associated from S phase (when DNA is replicated to generate two identical copies, the two chromatids) until anaphase. At this point, the two sister chromatids separate and travel to opposite poles in the dividing cell. Genetic and biochemical studies in yeast and in egg's extracts in Xenopus laevis identified

6321-468: Is implicated in sister chromatid cohesion, and its removal induces SAC activation. It has also been observed that other components of the ORC complex (such as orc5 in S. pombe ) are implicated in cohesion. However, the molecular pathway involving the ORC proteins seems to be additive to the cohesins' pathway, and it is mostly unknown. Centromeric cohesion resists the forces exerted by spindle microtubules towards

6468-400: Is independently required for SAC activation, it is unclear whether tension is an independent regulator of SAC, although it is clear that differing regulatory behaviors arise with tension. Once activated, the spindle checkpoint blocks anaphase entry by inhibiting the anaphase-promoting complex via regulation of the activity of mitotic checkpoint complex. The mechanism of inhibition of APC by

6615-400: 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

6762-416: Is often elevated in cancerous tissues for multiple kinds of cancer. It is correlated with aggressiveness in breast cancer: higher levels are associated with poorer outcomes. CDC20 overexpression has also been reported in lung, gastric, and pancreatic cancers. For gastric and pancreatic cancers, higher levels are correlated with tumor size, histological grade (the abnormality of the cells), and metastases to

6909-554: Is possible that the MAD2-CDC20 subcomplex acts as an initiator for MCC formation. BUBR1 depletion leads only to a mild reduction in Mad2-Cdc20 levels while Mad2 is required for the binding of BubR1-Bub3 to Cdc20. Nevertheless, BUBR1 is still required for checkpoint activation. The mechanism of formation for the MCC is unclear and there are competing theories for both kinetochore-dependent and kinetochore-independent formation. In support of

7056-513: Is present during the appropriate times of the cell cycle. In order for CDC20 to bind the APC/C, specific APC/C subunits must be phosphorylated by Cdk1 (among other Cdks). Therefore, when cdk activity is high in mitosis, and the cell must prepare to enter anaphase and exit mitosis, the APC/C complex is activated. Once active, APC/C promotes the degradation of Cdks by inactivating S/M cyclins. Cdk degradation brings about lower rates of APC/C phosphorylation and thus lower rates of CDC20 binding. In this way,

7203-452: Is recognized only if Cdc20, the activator subunit, is bound to the APC/C core. When securin, Cdc20, and E2 are all bound to APC/C E2 ubiquitinates securin and selectively degrades it. Securin degradation releases the protease Esp1p/separase, which degrades the cohesin rings that link the two sister chromatids, therefore promoting sister chromatids separation. It has been also shown that Polo/Cdc5 kinase phosphorylates serine residues next to

7350-474: Is regulated by ATP . Scc1p and Scc3p, however, would play a regulatory role. In S. cerevisiae , Pds1p (also known as securin ) regulates sister chromatids cohesion, because it binds and inhibits the protease Esp1p ( separin or separase ). When anaphase onset is triggered, the anaphase-promoting complex ( APC/C or Cyclosome) degrades securin. APC/C is a ring E3 ubiquitin ligase that recruits an E2 ubiquitin-conjugating enzyme loaded with ubiquitin. Securin

7497-403: 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

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7644-399: 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

7791-464: Is the "MAD2-template model", which depends on the kinetochore dynamics of MAD2 to create the MCC. MAD1 localizes to unattached kinetochores while binding strongly to MAD2. The localization of MAD2 and BubR1 to the kinetochore may also be dependent on the Aurora B kinase . Cells lacking Aurora B fail to arrest in metaphase even when chromosomes lack microtubule attachment. Unattached kinetochores first bind to

7938-446: Is thus derived from the process where MAD1-C-MAD2 acts as a template for the formation of C-MAD2-CDC20 copies. This sequestration of Cdc20 is essential for maintaining the spindle checkpoint. Several mechanisms exist to deactivate the SAC after correct bi-orientation of sister chromatids . Upon microtubule-kinetochore attachment, a mechanism of stripping via a dynein-dynein motor complex transports spindle checkpoint proteins away from

8085-410: 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 the intermediate template for the synthesis of a protein. The transmission of genes to an organism's offspring , is the basis of

8232-478: Is very abundant close to the centromeres, as it was shown in a study using chromatin immunoprecipitation. Classical cytologic observations suggested that sister chromatids are more strongly attached at heterochromatic regions, and this suggested that the special structure or composition of heterochromatin might favour cohesin recruitment. In fact, it has been shown that Swi6 (the homolog of HP-1 in S. pombe ) binds to methylated Lys 9 of histone H3 and promotes

8379-511: 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

8526-456: The anaphase promoting complex (APC/C), a large 11-13 subunit complex that initiates chromatid separation and entrance into anaphase . The APC/C protein complex has two main downstream targets. Firstly, it targets securin for destruction, enabling the eventual destruction of cohesin and thus sister chromatid separation. It also targets S and M-phase (S/M) cyclins for destruction, which inactivates S/M cyclin-dependent kinases (Cdks) and allows

8673-401: 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

8820-419: 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

8967-400: The lymph nodes . In colorectal cancer and non-small-cell lung carcinoma , it is associated with cancer stage , and thus has been proposed as a biomarker to help predict the prognosis for people with either cancer. Gene In biology , 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

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9114-549: 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

9261-475: 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

9408-750: 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

9555-449: 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,

9702-510: The APC/C complex inactivates itself by the end of mitosis. However, because the cell does not immediately enter the cell cycle, Cdks can not immediately be reactivated. Multiple different mechanisms inhibit Cdks in G1: Cdk inhibitor proteins are expressed, and cyclin gene expression is down-regulated. Importantly, cyclin accumulation is also prevented by Cdh1. CDC20-homologue 1 (Cdh1) plays a complementary role to CDC20 in cell cycle progression. During

9849-533: The APC/C, CDC20 can bind and activate it, allowing both the degradation of Cdks and the cleavage of cohesin. APC/C activity is dependent on CDC20 (and Cdh1), because CDC20 often binds the APC/C substrates directly. In fact, it is thought that CDC20 and Cdh1 (see below) are receptors for the KEN-box and D-box motifs on substrates. However, these sequences are normally not sufficient for ubiquitination and degradation; much remains to be learned about how CDC20 binds its substrate. The APC/C complex regulates itself so that it

9996-404: 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

10143-450: 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

10290-766: 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

10437-521: The MAD2-CDC20 subcomplex from its components. The SAC may also be deactivated by APC activation induced proteolysis . Since the SAC is not reactivated by the loss of sister-chromatid cohesion during anaphase, the proteolysis of cyclin B and inactivation of the CDK1-cyclin-B kinase also inhibits SAC activity. Degradation of MPS1 during anaphase prevents the reactivation of SAC after removal of sister-chromatid cohesion. After checkpoint deactivation and during

10584-506: 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 —

10731-520: The SAC also are characterized in multiple myeloma. Most solid tumors are also predominantly aneuploid. For colorectal cancer, BUB1 and BUBR1 and amplification of STK15 are key regulators that have been implicated in the genomic instability resulting in cancer. In breast cancer, the genetic form characterized by the BRCA-1 gene exhibits greater levels of genomic instability than sporadic forms. Experiments showed that BRCA-1 null mice have decreased expression of

10878-409: The SAC are also being pursued; strong interest has shifted towards the aurora kinase proteins. The kinase gene Aurora A when amplified acts as an oncogene overriding the SAC leading to abnormal initiation of anaphase and subsequent aneuploidy and also resistance to TAXOL . Excitingly, a small molecule inhibitor of Aurora A has shown antitumor effects in an in vivo model suggesting that this might be

11025-403: The SAC arresting the cell and eventually leading to its death. Taxol and Docetaxel , which can induce mitotic catastrophe , both are still used in the treatment of breast cancer, ovarian cancer and other types of epithelial cancer. However, these treatments are often characterized by high rates of side effects and drug resistance. Other targets within the network of regulators that influence

11172-449: The SAC include MAD1 , BUB1 , MPS1 , and Aurora B . For higher eukaryotes, additional regulators of the SAC include constituents of the ROD-ZW10 complex , p31 , MAPK , CDK1-cyclin-B , NEK2 , and PLK1 . [REDACTED] The SAC monitors the interaction between improperly connected kinetochores and spindle microtubules , and is maintained until kinetochores are properly attached to

11319-476: The SAC signaling pathway, but this step can only occur in the absence of microtubule attachment to the kinetochore. Endogenous Mps1 is shown to associate with the calponin-homology (CH) domain of Ndc80, which is located in the outer kinetochore region that is distant from the chromosome. Though Mps1 is docked in the outer kinetochore, it is still able to localize within the inner kinetochore and phosphorylate Spc105 because of flexible hinge regions on Ndc80. However,

11466-449: The SAC signaling pathway. This model is not applicable to SAC regulation in higher order organisms, including animals. A main facet of the mechanical switch mechanism is that in S. cerevisiae the structure of the kinetochore only allows for attachment of one microtubule. Kinetochores in animals, on the other hand, are much more complex meshworks that contain binding sites for a multitude of microtubules. Microtubule attachment at all of

11613-433: 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

11760-482: The binding of cohesin to the centromeric repeats in S. pombe . More recent studies indicate that the RNAi machinery regulates heterochromatin establishment, which in turn recruits cohesin to this region, both in S. pombe and in vertebrate cells. However, there must be other mechanisms than heterochromatin to ensure an augmented cohesion at centromeres, because S. cerevisiae lacks heterochromatin next to centromeres, but

11907-476: The cell cycle is blocked at the metaphase-to-anaphase transition. Using these drugs (see the review from Rieder and Palazzo in 1992 ), the putative control mechanism was named Spindle Assembly Checkpoint (SAC). This regulatory mechanism has been intensively studied since. Using different types of genetic studies, it has been established that diverse kinds of defects are able to activate the SAC: spindle depolymerization,

12054-556: The cell encounters a kinetochore, it may happen that the kinetochore will capture it, so that the chromosome will become attached to the spindle via the kinetochore of one of its sister chromatids. The chromosome plays an active role in the attachment of kinetochores to the spindle. Bound to the chromatin is a Ran guanine nucleotide exchange factor (GEF) that stimulates cytosolic Ran near the chromosome to bind GTP in place of GDP. The activated GTP-bound form of Ran releases microtubule-stabilizing proteins, such as TPX2, from protein complexes in

12201-403: The cell through mitosis. They must be degraded for cells to exit mitosis. Securin is a protein that inhibits separase , which in turn inhibits cohesin, a protein that holds sister chromatids together. Therefore, in order for anaphase to progress, securin must be inhibited so that cohesin can be cleaved by separase. These processes are dependent on both the APC/C and CDC20: When Cdks phosphorylate

12348-424: The cell to exit from mitosis . A closely related protein, Cdc20homologue-1 (Cdh1) plays a complementary role in the cell cycle. CDC20 appears to act as a regulatory protein interacting with many other proteins at multiple points in the cell cycle. It is required for two microtubule-dependent processes: nuclear movement prior to anaphase, and chromosome separation. CDC20, along with a handful of other Cdc proteins,

12495-411: The cell. The structure formed by the centrosomes and the microtubules is named mitotic spindle , due to its characteristic shape, holding the chromosomes between the two centrosomes. The sister chromatids stay together until anaphase , when each travels toward the centrosome to which it is attached. In this way, when the two daughter cells separate at the end of the division process, each one will contain

12642-467: The cells, while the cohesion between the sister chromatids opposes this force. At the metaphase to anaphase transition, this cohesion between sister chromatids is dissolved, and the separated chromatids are pulled to opposite sides of the cell by the spindle microtubules. The chromatids are further separated by the physical movement of the spindle poles themselves. Premature dissociation of the chromatids can lead to chromosome missegregation and aneuploidy in

12789-411: The centromeres produces an inhibitor to the anaphase onset when the two sister kinetochores are not under bipolar tension. Indeed, the available data suggested that the signal "wait to enter in anaphase" is produced mostly on or close to unattached kinetochores. However, the primary event associated to the kinetochore attachment to the spindle, which is able to inactivate the inhibitory signal and release

12936-408: The centrosome, and an end termed "plus" (+) end, with alternating phases of growth and retraction, exploring the center of the cell searching the chromosomes. Each chromatid has a special region, named the centromere , on top of which is assembled a proteic structure termed kinetochore , which is able to stabilize the microtubule plus end. Therefore, if by chance a microtubule exploring the center of

13083-436: 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

13230-402: 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

13377-447: The conclusion that increase in tumorigenesis is associated with defects other than aneuploidy alone. Cancer-associated mutations affecting known checkpoint genes like BUB1 or BUBR1 are actually rare. However, several proteins implicated in cancer have intersections to spindle assembly networks. Key tumor suppressors such as p53 also play a role in the spindle checkpoint. Absence of p53, the most commonly mutated gene in human cancer, has

13524-443: The cutting site for Scc1, and this phosphorylation would facilitate the cutting activity. Although this machinery is conserved through evolution, in vertebrates most cohesin molecules are released in prophase, independently of the presence of the APC/C, in a process dependent on Polo-like 1 ( PLK1 ) and Aurora B. Yet it has been shown that a small quantity of Scc1 remains associated to centromeres in human cells until metaphase, and

13671-436: The cytosol, which induces nucleation and polymerization of microtubules around the chromosomes. These kinetochore-derived microtubules, along with kinesin motor proteins in the outer kinetochore, facilitate interactions with the lateral surface of a spindle pole-derived microtubule. These lateral attachments are unstable, however, and must be converted to an end-on attachment. Conversion from lateral to end-on attachments allows

13818-622: The daughter cells. Thus, the job of the spindle checkpoint is to prevent this transition into anaphase until the chromosomes are properly attached, before the sister chromatids separate. In order to preserve the cell's identity and proper function, it is necessary to maintain the appropriate number of chromosomes after each cell division . An error in generating daughter cells with fewer or greater number of chromosomes than expected (a situation termed aneuploidy ), may lead in best case to cell death, or alternatively it may generate catastrophic phenotypic results. Examples include: Zirkle (in 1970)

13965-524: 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

14112-410: 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

14259-514: 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

14406-480: The first stage, which may be extended in the second stage if there are unattached kinetochores as well as other SAC proteins. However, there are lines of evidence which are in disfavor of the kinetochore-independent assembly. MCC has yet to be found during interphase , while MCC does not form from its constituents in X. laevis meiosis II extracts without the addition of sperm of nuclei and nocodazole to prevent spindle assembly. The leading model of MCC formation

14553-413: 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

14700-630: 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

14847-421: 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

14994-421: 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

15141-446: The growth and shrinkage of the microtubule plus-ends to be converted into forces that push and pull chromosomes to achieve proper bi-orientation. As it happens that sister chromatids are attached together and both kinetochores are located back-to-back on both chromatids, when one kinetochore becomes attached to one centrosome, the sister kinetochore becomes exposed to the centrosome located in the opposed pole; for this reason, in most cases

15288-415: 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 the phenotype of the individual. Most biological traits occur under

15435-418: The inhibition on S/M cyclins. CDC20 is also a part of, and regulated by, the spindle assembly checkpoint (SAC). This checkpoint ensures that anaphase proceeds only when the centromeres of all sister chromatids lined up on the metaphase plate are properly attached to microtubules. The checkpoint is held active by any unattached centromere; only when all centromeres are attached will anaphase commence. The APC/C

15582-481: The key spindle checkpoint protein MAD2 . For other cancers, more work is warranted to identify the causes of aneuploidy. Clearly variations in the physiological levels of these proteins (such as Mad2 or BubR1) are associated with aneuploidy and tumorigenesis, and this has been demonstrated using animal models . However, recent studies indicate that what seems to happen is a more complicated scenario: aneuploidy would drive

15729-504: The kinetochore assembly. Another regulator of checkpoint activation is kinetochore tension. When sister kinetochores are properly attached to opposite spindle poles, forces in the mitotic spindle generate tension at the kinetochores. Bi-oriented sister kinetochores stabilize the kinetochore-microtubule assembly whereas weak tension has a destabilizing effect. In response to incorrect kinetochore attachments such as syntelic attachment, where both kinetochores becomes attached to one spindle pole,

15876-415: The kinetochore binding sites is not necessary for deactivation of the SAC and progression to anaphase. Therefore, microtubule-attached and microtubule-unattached states coexist in the animal kinetochore while the SAC is inhibited. This model does not include a barrier that would prevent Mps1 associated with an attached kinetochore from phosphorylating Spc105 in an adjacent unattached kinetochore. Furthermore,

16023-454: The kinetochore is able to disrupt specific steps in SAC signaling. In an unattached kinetochore, the first step in the formation of the MCC is phosphorylation of Spc105 by the kinase Mps1. Phosphorylated Spc105 is then able to recruit the downstream signaling proteins Bub1 and 3; Mad 1,2, and 3; and Cdc20. Association with Mad1 at unattached kinetochores causes Mad2 to undergo a conformational change that converts it from an open form (O-Mad2) to

16170-466: The kinetochore-independent theory, MCC is detectable in S. cerevisiae cells in which core kinetocore assembly proteins have been mutated and cells in which the SAC has been deactivated, which suggests that the MCC could be assembled during mitosis without kinetochore localization. In one model, unattached prometaphase kinetochores can 'sensitize' APC to inhibition of MCC by recruiting the APC to kinetochores via

16317-566: The kinetochores of metaphase chromosomes. Not only does survivin inhibit apoptosis to promote tumorigenesis, but it has been implicated (through experimental knockout mice) as an important regulator of chromosome segregation, and late stage mitosis similar to its role in more primitive organisms. Other aspects of the spindle assembly checkpoint such as kinetochore attachment, microtubule function, and sister chromatid cohesion are likely to be defective as well to cause aneuploidy. Cancer cells have been observed to divide in multiple directions by evading

16464-510: The kinetochores. The stripped proteins, which include MAD1, MAD2, MPS1, and CENP-F , are then redistributed to the spindle poles . The stripping process is highly dependent on undamaged microtubule structure as well as dynein motility along microtubules. As well as functioning as a regulator of the C-MAD2 positive feedback loop, p31 also may act as a deactivator of the SAC. Unattached kinetochores temporarily inactivate p31 , but attachment reactivates

16611-533: The mechanical switch model proposes that end-on attachment of a microtubule to the kinetochore deactivates the SAC through two mechanisms. The presence of an attached microtubule increases the distance between the Ndc80 CH domain and Spc105. Additionally, Dam1/DASH, a large complex consisting of 160 proteins that forms a ring around the attached microtubule, acts as a barrier between the two proteins. Separation prevents interactions between Mps1 and Spc105 and thus inhibits

16758-401: The metaphase arrest, could be either the acquisition of microtubules by the kinetochore (as proposed by Rieder and collaborators in 1995 ), or the tension stabilizing the anchoring of microtubules to the kinetochores (as suggested by the experiments realized at Nicklas' lab ). Subsequent studies in cells containing two independent mitotic spindles in a sole cytoplasm showed that the inhibitor of

16905-464: The metaphase plate and delocalization of the proteins in the chromosomal passenger complex , which contains the protein Aurora B. The proposed structure for the cohesin complex suggests that this complex connects directly both sister chromatids. In this proposed structure, the SMC components of cohesin play a structural role, so that the SMC heterodimer may function as a DNA binding protein, whose conformation

17052-482: The metaphase-to-anaphase transition is generated by unattached kinetochores and is not freely diffusible in the cytoplasm. Yet in the same study it was shown that, once the transition from metaphase to anaphase is initiated in one part of the cell, this information is extended all along the cytoplasm , and can overcome the signal "wait to enter in anaphase" associated to a second spindle containing unattached kinetochores. When cells are ready to divide, because cell size

17199-651: The microtubule-severing KINI kinesin MCAK, the DASH complex , and the Ndc80/Hec1 complex at the microtubule-kinetochore interface. The Aurora-B/Ipl1 kinase is also critical in correcting merotelic attachments, where one kinetochore is simultaneously attached to both spindle poles. Merotelic attachments generate sufficient tension and are not detected by the SAC, and without correction, may result in chromosome mis-segregation due to slow chromatid migration speed. While microtubule attachment

17346-672: The mitotic checkpoint complex is poorly understood, although it is hypothesized that the MCC binds to APC as a pseudosubstrate using the KEN-box motif in BUBR1 . At the same time that mitotic checkpoint complex is being activated, the centromere protein CENP-E activates BUBR1, which also blocks anaphase. The mitotic checkpoint complex is composed of BUB3 together with MAD2 and MAD3 bound to Cdc20 . MAD2 and MAD3 have distinct binding sites on CDC20, and act synergistically to inhibit APC/C. The MAD3 complex

17493-442: The molecular role of CDC20 remained elusive until the discovery of the APC/C in 1995. CDC20 is a protein related to the beta subunit of heterotrimeric G proteins . Near its C-terminus it contains seven WD40 repeats , which are multiple short, structural motifs of around 40 amino acids that often play a role in binding with larger protein complexes. In the case of CDC20, they arrange into a seven-bladed beta propeller. The human CDC20

17640-530: The most important interaction of CDC20 is with the Anaphase Promoting Complex. The APC/C is a large E3 ubiquitin ligase, which triggers the metaphase to anaphase transition by marking select proteins for degradation. The two main targets of the APC/C are the S/M cyclins and the protein securin. S/M cyclins activate cyclin-dependent kinases (Cdks), which have a vast array of downstream effects that work to guide

17787-511: The normal anaphase of the cell cycle, the anaphase promoting complex is activated through decreasing MCC activity. When this happens the enzyme complex polyubiquitinates the anaphase inhibitor securin . The ubiquitination and destruction of securin at the end of metaphase releases the active protease called separase. Separase cleaves the cohesion molecules that hold the sister chromatids together to activate anaphase. A new mechanism has been suggested to explain how end-on microtubule attachment at

17934-413: 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

18081-431: 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

18228-410: The poles, which generate tension between sister kinetochores. In turn, this tension stabilizes the attachment microtubule-kinetochore, through a mechanism implicating the protein Aurora B (a review about this issue : Hauf and Watanabe 2004 ). Indeed, a decrease in the cellular levels of cohesin generates the premature separation of sister chromatids, as well as defects in chromosome congression at

18375-432: The presence of a functional centromere induces an increase of cohesin association in a contiguous region, spanning 20-50kb. In this direction, Orc2 (one protein included in the origin recognition complex , ORC, implicated in the initiation of DNA replication during S phase ) is also located on kinetochores during mitosis in human cells; in agreement with this localization, some observations indicate that Orc2 in yeast

18522-435: The presence of dicentric chromosomes (with two centromeres), centromeres segregating in an aberrant way, defects in the spindle pole bodies in S. cerevisiae , defects in the kinetochore proteins, mutations in the centromeric DNA or defects in the molecular motors active during mitosis. A summary of these observations can be found in the article from Hardwick and collaborators in 1999. Using its own observations, Zirkle

18669-449: The proper chromosome segregation in each cell cycle preventing chromosome instability (CIN) also known as genome instability . Genomic integrity is now appreciated at several levels where some tumors display instability manifested as base substitutions, insertions, and deletions, while the majority displays gains or losses of whole chromosomes. Due to the fact that alterations in mitotic regulatory proteins can lead to aneuploidy and this

18816-489: The protein Shugoshin (Sgo1), avoiding their release during prophase. To be able to function as protector for the centromeric cohesion, Sgo1 must be inactivated at the beginning of anaphase, as well as Pds1p. In fact, both Pds1p and Sgo1 are substrates of APC/C in vertebrates. In mouse oocytes , DNA damage induces meiotic prophase I arrest that is mediated by the spindle assembly checkpoint. Arrested oocytes do not enter

18963-413: The protein and inhibits MAD2 activation, possibly by inhibitory phosphorylation. Another possible mechanism of SAC inactivation results from energy-dependent dissociation of the MAD2-CDC20 complex through non-degradative ubiquitylation of CDC20. Conversely, the de-ubiquitylating enzyme protectin is required to maintain the SAC. Thus, unattached kinetochores maintain the checkpoint by continuously recreating

19110-403: The second kinetochore becomes associated to the centrosome in the opposed pole, via its microtubules, so that the chromosomes become "bi-oriented", a fundamental configuration (also named amphitelic ) to ensure that chromosome segregation will take place correctly when the cell will divide. Occasionally, one of the two sister kinetochores may attach simultaneously to MTs generated by both poles,

19257-593: The spindle assembly checkpoint might be regarded as a possible target for anti-tumour therapy. This is a much underappreciated fact since mutations in specific genes known as oncogenes or tumor suppressor are primarily thought to be behind genetic instability and tumorigenesis. Usually the various checkpoints in the cell cycle take care of genomic integrity via highly conserved redundant mechanisms that are important for maintaining cellular homeostasis and preventing tumorigenesis. Several spindle assembly checkpoint proteins act both as positive and negative regulators to ensure

19404-534: The spindle assembly checkpoint resulting in multipolar mitoses. The multipolar metaphase-anaphase transition occurs through an incomplete separase cycle that results in frequent nondisjunction events which amplify aneuploidy in cancer cells. Advances in this field have led to the introduction of development of some therapies targeted at spindle assembly defects. Older treatments such as vinca alkaloids and taxanes target microtubules that accompany mitotic spindle formation via disruption of microtubule dynamics which engage

19551-450: The spindle. During prometaphase , CDC20 and the SAC proteins concentrate at the kinetochores before attachment to the spindle assembly. These proteins keep the SAC activated until they are removed and the correct kinetochore-microtubule attachment is made. Even a single unattached kinetochore can maintain the spindle checkpoint. After attachment of microtubule plus-ends and formation of kinetochore microtubules, MAD1 and MAD2 are depleted from

19698-467: 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

19845-489: The subsequent stage, anaphase I. DNA double strand breaks, UVB and ionizing radiation induced DNA damage cause an effective block to anaphase promoting complex activity. This checkpoint may help prevent oocytes with damaged DNA from progressing to become fertilizable mature eggs. During prophase arrest mouse oocytes appear to use both homologous recombinational repair and non-homologous end joining to repair DNA double-strand breaks. The spindle assembly checkpoint (SAC)

19992-461: 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

20139-805: 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

20286-436: 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,

20433-412: 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)

20580-558: The time of APC/C activity, Cdh1 is phosphorylated and cannot bind to the APC/C. After metaphase, however, S/M-Cdks are inactivated by APC/C, and Cdh1 can exist in a non-phosphorylated state and bind the APC/C. This enables the APC/C to continue to degrade S/M cyclins (and thus S/M Cdks) until they are needed again in the next S-phase. How can S/M cyclins reappear to shepherd the cell into mitosis? The APC/C does not recognize G1/S cyclins. Their concentration rises during G1, activating G1/S Cdks, which in turn phosphorylate Cdh1 and gradually relieve

20727-471: The weak tension generated destabilizes the incorrect attachment and allows the kinetochore to reattach correctly to the spindle body. During this process, kinetochores that are attached to the mitotic spindle but that are not under tension trigger the spindle checkpoint. Aurora-B/Ipl1 kinase of the chromosomal passenger complex functions as the tensions sensor in improper kinetochore attachments. It detects and destabilizes incorrect attachments through control of

20874-442: The yeast Dam1/DASH complex is not present in animal cells. When the spindle checkpoint misfunctions, this can lead to chromosome missegregation, aneuploidy and even tumorigenesis . Transformation occurs and is accelerated when maintenance of genomic integrity breaks down especially at the gross level of whole chromosomes or large portions of them. In fact, aneuploidy is the most common characteristic of human solid tumors and thus

21021-459: Was discovered in the early 1970s when Hartwell and colleagues made cell-division cycle mutants that failed to complete major events in the cell cycle in the yeast strain S. cerevisiae . Hartwell found mutants that did not enter anaphase and thus could not complete mitosis; this phenotype could be traced back to the CDC20 gene. However, even after the biochemistry of the protein was eventually elucidated,

21168-446: 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

21315-404: Was one of the first researchers to observe that, when just one chromosome is retarded to arrive at the metaphase plate, anaphase onset is postponed until some minutes after its arrival. This observation, together with similar ones, suggested that a control mechanism exists at the metaphase-to-anaphase transition. Using drugs such as nocodazole and colchicine , the mitotic spindle disassembles and

21462-430: 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

21609-474: Was the first to propose that "some (…) substance, necessary for the cell to proceed to anaphase, appears some minutes after C (moment of the arrival of the last chromosome to the metaphase plate), or after a drastic change in the cytoplasmic condition, just at C or immediately after C", suggesting that this function is located on kinetochores unattached to the mitotic spindle. McIntosh extended this proposal, suggesting that one enzyme sensitive to tension located at

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