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50-427: Cells from a person with Bloom syndrome exhibit a striking genomic instability that includes excessive crossovers between homologous chromosomes and sister chromatid exchanges (SCEs). The condition was discovered and first described by New York dermatologist Dr. David Bloom in 1954. Bloom syndrome has also appeared in the older literature as Bloom–Torre–Machacek syndrome . The most prominent feature of Bloom syndrome

100-659: A Toprim domain (a Rossman fold known to coordinate Magnesium ions), domain IV and domain III each consist of a helix-turn-helix (HTH) domain; the catalytic tyrosine resides on the HTH of domain III. Domain II is a flexible bridge between domains III and IV. The structure of type IA topoisomerase resembles a lock, with Domains I, III and IV lying on the bottom of the structure. The structure of topo III (see below) bound to single-stranded DNA (pdb id = 1I7D) shows how

150-542: A combination of deficiencies in the expression of two or more genes leads to cell death, whereas a deficiency in only one of these genes does not. The deficiencies can arise through mutation, epigenetic alteration or by inhibition of a gene's expression. Topoisomerase 1 inhibition is synthetically lethal with deficiency of expression of certain DNA repair genes. In human patients the deficient DNA repair genes include WRN and MRE11 . In pre-clinical studies related to cancer,

200-629: A four criss-crossed beta-strands surrounded by four alpha-helices that are arranged in a Rossmann fold Type I topoisomerases are ATP -independent enzymes (except for reverse gyrase ), and can be subdivided according to their structure and reaction mechanisms: type IA (bacterial and archaeal topoisomerase I, topoisomerase III and reverse gyrase) and type IB (eukaryotic topoisomerase I and topoisomerase V). These enzymes are primarily responsible for relaxing positively and/or negatively supercoiled DNA, except for reverse gyrase, which can introduce positive supercoils into DNA. DNA topoisomerases regulate

250-416: A gene that could cause Bloom Syndrome in their offspring. Bloom syndrome has no specific treatment; however, avoiding sun exposure and using sunscreens can help prevent some of the cutaneous changes associated with photo-sensitivity . Efforts to minimize exposure to other known environmental mutagens are also advisable in multiple forms. Bloom syndrome is an extremely rare disorder in most populations and

300-512: A malignant neoplasm, and there have been 227 malignancies. The types of cancer and the anatomic sites at which they develop resemble the cancers that affect persons in the general population. The age of diagnosis for these cancers is earlier than for the same cancer in normal persons, and many persons with Bloom syndrome have been diagnosed with multiple cancers. The average life span is approximately 27 years. The most common cause of death in Bloom syndrome

350-417: A pathway that does not involve Holliday junction intermediates. During oogenesis in the nematode Caenorhabditis elegans the sister chromatid, or even the same DNA molecule, can serve as a meiotic repair template for both crossover and non- crossover recombination . Non-crossover events are the most frequent recombination outcome. For DNA double strand breaks induced throughout meiotic prophase I,

400-505: A single break in DNA and pass a second strand or duplex through the break. This strand passage mechanism shares several features with type IIA topoisomerases. They both form a 5' phosphotyrosine intermediate, and require a divalent metal ion to perform its work. Unlike type II topoisomerases , type IA topoisomerases do not use energy to do its work (with the notable exception of reverse gyrase, see below). Type IA topoisomerases have several domains, often number Domain 1-4. Domain I contains

450-452: A single gate (in contrast with type II topoisomerases). First, the single-stranded DNA binds domain III and I. The catalytic tyrosine cleaves the DNA backbone, creating a transient 5' phosphotyrosine intermediate. The break is then separated, using domain II as a hinge, and a second duplex or strand of DNA is passed through. Domain III and I close and the DNA is re-annealed. In contrast to type IA topoisomerases, type 1B Topoisomerase solves

500-402: A striking genomic instability that is characterized by hyper-recombination and hyper-mutation. Human BLM cells are sensitive to DNA damaging agents such as UV and methyl methanesulfonate, indicating deficient repair capability. At the level of the chromosomes, the rate of sister chromatid exchange in Bloom's syndrome is approximately 10 fold higher than normal and quadriradial figures, which are

550-567: Is a remarkable lack in interest in food. There are endocrine disturbances, particularly abnormalities of carbohydrate metabolism , insulin resistance and susceptibility to type 2 diabetes , dyslipidemia , and compensated hypothyroidism . Persons with Bloom syndrome exhibit a paucity of subcutaneous fat. There is reduced fertility, characterized by a failure in males to produce sperm (azoospermia) and premature cessation of menses (premature menopause ) in females. Despite these reductions, several women with Bloom syndrome have had children, and there

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600-532: Is a single report of a male with Bloom syndrome bearing children. Although some persons with Bloom syndrome can struggle in school with subjects that require abstract thought, there is no evidence that intellectual disability is more common in Bloom syndrome than in other people. The most serious and frequent complication of Bloom syndrome is cancer . In the 281 persons followed by the Bloom Syndrome Registry, 145 persons (51.6%) have been diagnosed with

650-513: Is associated with a high risk of cancer in affected individuals. The cancer predisposition is characterized by 1) broad spectrum, including leukemias, lymphomas, and carcinomas, 2) early age of onset relative to the same cancer in the general population, and 3) multiplicity, that is, synchronous or metachronous cancers. There is at least one person with Bloom syndrome who had five independent primary cancers. Persons with Bloom syndrome may develop cancer at any age. The average age of cancer diagnoses in

700-446: Is described as erythematous , that is red and inflamed, and telangiectatic , that is characterized by dilated blood vessels at the skin's surface. The rash commonly also affects the backs of the hands and neck, and it can develop on any other sun-exposed areas of the skin. The rash is variably expressed, being present in a majority but not all persons with Bloom syndrome, and it is on average less severe in females than in males. Moreover,

750-510: Is from cancer. Other complications of the disorder include chronic obstructive lung disease and type 2 diabetes. There are a variety of excellent sources for more detailed clinical information about Bloom syndrome. There is a closely related entity that is now referred to as Bloom-syndrome-like disorder (BSLD) which is caused by mutations in components of the same protein complex to which the BLM gene product belongs, including TOP3A , which encodes

800-513: Is high-pitched and squeaky. There are a variety of other features that are commonly associated with Bloom syndrome. There is a moderate immune deficiency , characterized by deficiency in certain immunoglobulin classes and a generalized proliferative defect of B and T cells . The immune deficiency is thought to be the cause of recurrent pneumonia and middle ear infections in persons with the syndrome. Infants can exhibit frequent gastrointestinal upsets, with reflux, vomiting, and diarrhea, and there

850-459: Is involved in communicating the hydrolysis of ATP to the introduction of positive supercoils. The topo III variant is likewise very interesting because it has zinc-binding motifs that is thought to bind single-stranded DNA. Topo III has been identified to be associated with the BLM (for Bloom Syndrome) helicase during recombination. Type IA topoisomerases operate through a strand-passage mechanism, using

900-410: Is proportional small size. The small size is apparent in utero. At birth, neonates exhibit rostral to caudal lengths, head circumferences, and birth weights that are typically below the third percentile. The second most commonly noted feature is a rash on the face that develops early in life as a result of sun exposure. The facial rash appears most prominently on the cheeks, nose, and around the lips. It

950-444: Is that uncoiling of the DNA is torque-driven and proceeds until religation occurs. No data suggest that Topo IB "controls" the swiveling insofar as that it has a mechanism in place that triggers religation after a specific number of supercoils removed. On the contrary, single-molecule experiments suggest that religation is a random process and has some probability of occurring each time the swiveling 5'-OH end comes in close proximity with

1000-482: Is the exchange of genetic material between two identical sister chromatids . It was first discovered by using the Giemsa staining method on one chromatid belonging to the sister chromatid complex before anaphase in mitosis . The staining revealed that few segments were passed to the sister chromatid which were not dyed. The Giemsa staining was able to stain due to the presence of bromodeoxyuridine analogous base which

1050-404: Is the founding member, and so far the only member, of the type IC topoisomerase, although some authors suggest it may have viral origins. The crystal structure of topo V was solved. Type IC topoisomerases work through a controlled rotary mechanism, much like type IB topoisomerases (pdb ID = 2CSB and 2CSD ), but the fold is unique. All topoisomerases form a phosphotyrosine intermediate between

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1100-446: The type I topoisomerase , topoisomerase 3 alpha, RMI1 , and RMI2 . The features of BSLD include small size and dermatologic findings, such as cafe-au-lait spots, and the presence of the once pathognomonic elevated SCEs is reported for persons with mutations in TOP3A and RMI1 . Bloom syndrome shares some features with Fanconi anemia possibly because there is overlap in the function of

1150-446: The DNA of daughter chromosomes after DNA replication, and relax DNA. These enzymes have several functions: to remove DNA supercoils during transcription and DNA replication ; for strand breakage during recombination ; for chromosome condensation; and to disentangle intertwined DNA during mitosis . This domain assumes a beta(2)-alpha-beta-alpha-beta(2) fold, with a left-handed crossover between strands beta2 and beta3. It has

1200-411: The HTH and Toprim domain are coordinated about the DNA. There are several variants of Type IA topoisomerases, differing by appendages attached to the main core (sometimes referred to as the "topo-fold"). Members of this subclass include topo I, topo III (which contain additional Zinc-binding motifs), and reverse gyrase. Reverse gyrase is particularly interesting because an ATPase domain, which resembles

1250-402: The attachment site of the enzyme-linked 3'-end. Type IB topoisomerases were originally identified in eukaryotes and in viruses. Viral topo I is unique because it binds DNA in a sequence-specific manner. See the article TOP1 for further details on this well-studied type 1B topoisomerase. A third type of topoisomerase I was identified, topo V, in the archaeon Methanopyrus kandleri . Topo V

1300-596: The base pairs flanking the topoisomerase-induced cleavage site and poisons (inactivates) the topoisomerase 1 enzyme. Upon bacteriophage (phage) T4 infection of its bacterial host, Escherichia coli , the phage genome specifies a gene product (gp55.2) that inhibits the bacterial topoisomerase I. Gp55.2 binds DNA and specifically blocks the relaxation of negatively supercoiled DNA by topoisomerase I. This inhibition appears to be an adaptation to subtly modulate host topoisomerase I activity during infection to ensure optimal phage yield. Synthetic lethality arises when

1350-459: The budding yeast Saccharomyces cerevisiae is primarily a result of DNA repair processes responding to spontaneous or induced damages that occur during vegetative growth. } (Also reviewed in Bernstein and Bernstein, pp 220–221 ). In order for yeast cells to repair damage by homologous recombination , there must be present, in the same nucleus, a second DNA molecule containing sequence homology with

1400-548: The capacity to repair more DNA damage than do homologs. [REDACTED] The genomes of diploid organisms in natural populations are highly polymorphic for insertions and deletions . During meiosis double-strand breaks (DSBs) that form within such polymorphic regions must be repaired by inter- sister chromatid exchange, rather than by inter-homolog exchange. A molecular-level study of recombination during budding yeast meiosis has shown that recombination events initiated by DSBs in regions that lack corresponding sequences in

1450-411: The catalytic tyrosine of the enzyme and the scissile phosphoryl of the DNA backbone. This intermediate is isoenergetic, meaning that the forward cleavage reaction and the backward religation reaction are both energetically equal. As such, no outside energy source is necessary to conduct this reaction. As topoisomerases generate breaks in DNA, they are targets of small-molecule inhibitors that inhibit

1500-484: The cohort is approximately 26 years old. When a cell prepares to divide to form two cells, the chromosomes are duplicated so that each new cell will get a complete set of chromosomes. The duplication process is called DNA replication . Errors made during DNA replication can lead to mutations. The BLM protein is important in maintaining the stability of the DNA during the replication process. Lack of BLM protein or protein activity leads to an increase in mutations; however,

1550-820: The cytologic manifestations of crossing-over between homologous chromosome, are highly elevated. Other chromosome manifestations include chromatid breaks and gaps, telomere associations, and fragmented chromosomes. The hyper-recombination can also be detected by molecular assays The BLM gene encodes a member of the protein family referred to as RecQ helicases . The diffusion of BLM has been measured to 1.34 μ m 2 s {\displaystyle {\tfrac {\mathrm {\mu m} ^{2}}{\mathrm {s} }}} in nucleoplasm and 0.13 μ m 2 s {\displaystyle \textstyle {\tfrac {\mathrm {\mu m} ^{2}}{\mathrm {s} }}} at nucleoli DNA helicases are enzymes that attach to DNA and temporarily unravel

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1600-468: The dissolvasome. Disruption of the proper assembly of the Bloom Syndrome complex leads to genome stability, genetic dependence on cellular nucleases GEN1 and MUS81, and loss of normal cell growth. Bloom-like phenotypes have been associated with mutations in topoisomerase III alpha, RMI1 and RMI2 genes. As noted above, there is greatly elevated rate of mutation in Bloom syndrome and the genomic instability

1650-435: The double helix of the DNA molecule. DNA helicases function in DNA replication and DNA repair. BLM very likely functions in DNA replication, as cells from persons with Bloom syndrome exhibit multiple defects in DNA replication, and they are sensitive to agents that obstruct DNA replication. The BLM helicase is a member of a protein complex with topoisomerase III alpha, RMI1 and RMI2, also known as BTRR, Bloom Syndrome complex or

1700-468: The enzyme. Type 1 topoisomerase is inhibited by irinotecan , topotecan , hexylresorcinol and camptothecin . The human topoisomerase type IB enzyme forms a covalent 3'-phosphotyrosine intermediate, the topoisomerase 1-cleavage-complex (Top1cc). The active irinotecan metabolite, SN-38 , acts by trapping (making a ternary complex with) a subset of Top1cc, those with a guanine +1 in the DNA sequence. One irinotecan-derived SN-38 molecule stacks against

1750-458: The frequency of the disease has not been measured in most populations. However, the disorder is relatively more common amongst people of Central and Eastern European Ashkenazi Jewish background. Approximately 1 in 48,000 Ashkenazi Jews are affected by Bloom syndrome, who account for about one-third of affected individuals worldwide. The Bloom's Syndrome Registry lists 283 individuals reported to have this rare disorder (as of 2020), collected from

1800-445: The helicase-like domain of the Rho transcription factor, is attached (the structure of reverse gyrase was solved by Rodriguez and Stock, EMBO J 2002). The enzyme uses the hydrolysis of ATP to introduce positive supercoils and overwinds DNA, a feature attractive in hyperthermophiles, in which reverse gyrase is known to exist. Rodriguez and Stock have done further work to identify a "latch" that

1850-471: The molecular mechanism(s) by which BLM maintains stability of the chromosomes is still a very active area of research. Persons with Bloom syndrome have an enormous increase in exchange events between homologous chromosomes or sister chromatids (the two DNA molecules that are produced by the DNA replication process); and there are increases in chromosome breakage and rearrangements compared to persons who do not have Bloom's syndrome. Direct connections between

1900-400: The molecular processes in which BLM operates and the chromosomes themselves are under investigation. The relationships between molecular defects in Bloom syndrome cells, the chromosome mutations that accumulate in somatic cells (the cells of the body), and the many clinical features seen in Bloom syndrome are also areas of intense research. Bloom syndrome is diagnosed using any of three tests -

1950-516: The non-sister homolog are efficiently repaired by inter-sister chromatid recombination. [REDACTED] This recombination occurs with the same timing as inter-homolog recombination, but with reduced (2- to 3-fold) yields of Holliday junction joint molecules. This study, and comparable evidence from other organisms (e.g. Peacock ), indicates that inter-sister recombination occurs frequently during meiosis, and up to one-third of all recombination events occur between sister chromatids, although mainly by

2000-522: The number of topological links between two DNA strands (i.e. change the number of superhelical turns) by catalysing transient single- or double-strand breaks, crossing the strands through one another, then resealing the breaks. DNA topoisomerases are divided into two classes: type I enzymes ( EC ; topoisomerases I, III and V) break single-strand DNA, and type II enzymes ( EC ; topoisomerases II, IV and VI) break double-strand DNA. Type IA topoisomerases, historically said to be found in prokaryotes, create

2050-445: The presence of quadriradial (Qr, a four-armed chromatid interchange) in cultured blood lymphocytes, and/or the elevated levels of sister chromatid exchange in cells of any type, and/or the mutation in the BLM gene. The US Food and Drug Administration (FDA) announced on February 19, 2015, that they have authorized marketing of a direct-to-consumer genetic test from 23andMe . The test is designed to identify healthy individuals who carry

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2100-430: The problem of overwound and underwound (also referred to as positively or negatively supercoiled) DNA through a hindered rotary mechanism. Crystal structures, biochemistry, and single molecule experiments have contributed to a general mechanism. The enzyme first wraps around DNA and creates a single, 3' phosphotyrosine intermediate. The 5' end is then free to rotate, twisting it about the other strand, to relax DNA until

2150-506: The proteins mutated in this related disorder. Bloom syndrome is an autosomal recessive disorder, caused by mutations in the maternally- and paternally-derived copies of the gene BLM . As in other autosomal recessive conditions, the parents of an individual with Bloom syndrome do not necessarily exhibit any features of the syndrome. The mutations in BLM associated with Bloom syndrome are nulls and missense mutations that are catalytically inactive. The cells from persons with Bloom syndrome exhibit

2200-469: The reaction between the tyrosine residue at the active site of the enzyme with the phosphodiester DNA backbone simply replaces one phosphomonoester bond with another. The topoisomerase also does not use ATP during uncoiling of the DNA; rather, the torque present in the DNA drives the uncoiling and proceeds on average energetically downhill. Recent single molecule experiments have confirmed what bulk-plasmid relaxation experiments have proposed earlier, which

2250-590: The region to be repaired. In a diploid cell in G1 phase of the cell cycle, such a molecule is present in the form of the homologous chromosome. However, in the G2 phase of the cell cycle (following DNA replication), a second homologous DNA molecule is also present: the sister chromatid . Evidence indicates that, due to the special nearby relationship they share, sister chromatids are not only preferred over distant homologous chromatids as substrates for recombinational repair, but have

2300-908: The sister or intra-chromatid substrate is available as a recombinational repair partner. Type I topoisomerase In molecular biology Type I topoisomerases are enzymes that cut one of the two strands of double-stranded DNA, relax the strand, and reanneal the strand. They are further subdivided into two structurally and mechanistically distinct topoisomerases: type IA and type IB. Historically, type IA topoisomerases are referred to as prokaryotic topo I, while type IB topoisomerases are referred to as eukaryotic topoisomerase. This distinction, however, no longer applies as type IA and type IB topoisomerases exist in all domains of life. Functionally, these subclasses perform very specialized functions. Prokaryotic topoisomerase I (topo IA) can only relax negative supercoiled DNA, whereas eukaryotic topoisomerase I (topo IB) can introduce positive supercoils, separating

2350-402: The sun sensitivity can resolve in adulthood. There are other dermatologic changes, including hypo-pigmented and hyper-pigmented areas, cafe-au-lait spots , and telangiectasias , which can appear on the face and on the ocular surface. There is a characteristic facial appearance that includes a long, narrow face; prominent nose, cheeks, and ears; and micrognathism or undersized jaw. The voice

2400-584: The time it was first recognized in 1954. The registry was developed as a surveillance mechanism to observe the effects of cancer in the patients, which has shown 122 individuals have been diagnosed with cancer. It also acts as a report to show current findings and data on all aspects of the disorder. see also Template:Congenital malformations and deformations of skin appendages , Template:Phakomatoses , Template:Pigmentation disorders , Template:DNA replication and repair-deficiency disorder Sister chromatid exchange Sister chromatid exchange ( SCE )

2450-409: The topoisomerase re-ligates the broken strands. The structure of topo IB bound to DNA has been solved (pdb id = 1A36). Topo IB is composed of an NTD, a capping lobe, a catalytic lobe, and a C-terminal domain. The capping lobe and catalytic lobe wrap around the DNA. Relaxation is not an active process and energy (in the form of ATP ) is not spent during the nicking or ligation steps; this is because

2500-705: Was introduced to the desired chromatid. The reason for the (SCE) is not known but it is required and used as a mutagenic testing of many products. Four to five sister chromatid exchanges per chromosome pair, per mitosis is in the normal distribution, while 14–100 exchanges is not normal and presents a danger to the organism. SCE is elevated in pathologies including Bloom syndrome , having recombination rates ~10–100 times above normal, depending on cell type. Frequent SCEs may also be related to formation of tumors . Sister chromatid exchange has also been observed more frequently in B51 (+) Behçet's disease . Mitotic recombination in

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