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PloS One 2012Centromeres are specialized chromosome domains that control chromosome segregation during mitosis, but little is known about the mechanisms underlying the maintenance of...
Centromeres are specialized chromosome domains that control chromosome segregation during mitosis, but little is known about the mechanisms underlying the maintenance of their integrity. Centromeric ultrafine anaphase bridges are physiological DNA structures thought to contain unresolved DNA catenations between the centromeres separating during anaphase. BLM and PICH helicases colocalize at these ultrafine anaphase bridges and promote their resolution. As PICH is detectable at centromeres from prometaphase onwards, we hypothesized that BLM might also be located at centromeres and that the two proteins might cooperate to resolve DNA catenations before the onset of anaphase. Using immunofluorescence analyses, we demonstrated the recruitment of BLM to centromeres from G2 phase to mitosis. With a combination of fluorescence in situ hybridization, electron microscopy, RNA interference, chromosome spreads and chromatin immunoprecipitation, we showed that both BLM-deficient and PICH-deficient prometaphase cells displayed changes in centromere structure. These cells also had a higher frequency of centromeric non disjunction in the absence of cohesin, suggesting the persistence of catenations. Both proteins were required for the correct recruitment to the centromere of active topoisomerase IIα, an enzyme specialized in the catenation/decatenation process. These observations reveal the existence of a functional relationship between BLM, PICH and topoisomerase IIα in the centromere decatenation process. They indicate that the higher frequency of centromeric ultrafine anaphase bridges in BLM-deficient cells and in cells treated with topoisomerase IIα inhibitors is probably due not only to unresolved physiological ultrafine anaphase bridges, but also to newly formed ultrafine anaphase bridges. We suggest that BLM and PICH cooperate in rendering centromeric catenates accessible to topoisomerase IIα, thereby facilitating correct centromere disjunction and preventing the formation of supernumerary centromeric ultrafine anaphase bridges.
Topics: Anaphase; Antigens, Neoplasm; Cell Cycle Proteins; Centromere; Chromosomal Proteins, Non-Histone; Chromosomes; DNA Helicases; DNA Topoisomerases, Type II; DNA, Catenated; DNA-Binding Proteins; G2 Phase; HeLa Cells; Humans; Mitosis; Mutagenesis, Site-Directed; Prometaphase; RNA Interference; RNA, Small Interfering; RecQ Helicases; Cohesins
PubMed: 22563370
DOI: 10.1371/journal.pone.0033905 -
Pediatric Blood & Cancer Feb 2021The treatment of malignancy in cancer predisposition syndromes that also confer exquisite sensitivity to standard chemotherapy and radiation regimens remains a...
The treatment of malignancy in cancer predisposition syndromes that also confer exquisite sensitivity to standard chemotherapy and radiation regimens remains a challenge. Bloom syndrome is one such disorder that is caused by a defect in DNA repair, predisposing to the development of early-onset age-related medical conditions and malignancies. We report on two patients with Bloom syndrome who responded well to chemotherapy despite significant alterations to standard protocols necessitated by hypersensitivity. Both patients experienced severe toxicities and exacerbation of endocrine comorbidities during chemotherapy. A multidisciplinary team of oncologists and endocrinologists is best suited to care for this patient population.
Topics: Antineoplastic Agents; Bloom Syndrome; DNA Repair; Endocrine System Diseases; Female; Humans; Male; Neoplasms; RecQ Helicases; Young Adult
PubMed: 33226170
DOI: 10.1002/pbc.28815 -
Lung India : Official Organ of Indian... Jul 2009We report a case of a 24-year old male presented with cough and breathlessness with diabetes mellitus and diagnosed as a case of bloom syndrome. He was a product of...
We report a case of a 24-year old male presented with cough and breathlessness with diabetes mellitus and diagnosed as a case of bloom syndrome. He was a product of consanguineous marriage, having short stature, dolicocephaly, polydactyly, prominent nose with telangiectasia face. The respiratory system examination revealed bilateral coarse crepitations and wheezes and the chest X-ray revealed emphysema with right middle zone inhomogenous opacity. Also, CT thorax examination revealed bilateral cystic bronchiectasis with bronchiolitis obliterans. Bloom's syndrome was diagnosed on the basis of clinical features.
PubMed: 20442845
DOI: 10.4103/0970-2113.53234 -
The Journal of Biological Chemistry Jun 2002The RecQ helicase family comprises a conserved group of proteins implicated in several aspects of DNA metabolism. Three of the family members are defective in heritable...
The RecQ helicase family comprises a conserved group of proteins implicated in several aspects of DNA metabolism. Three of the family members are defective in heritable diseases characterized by abnormal growth, premature aging, and predisposition to malignancies. These include the WRN and BLM gene products that are defective in Werner and Bloom syndromes, disorders which share many phenotypic and cellular characteristics including spontaneous genomic instability. Here, we report a physical and functional interaction between BLM and WRN. These proteins were coimmunoprecipitated from a nuclear matrix-solubilized fraction, and the purified recombinant proteins were shown to interact directly. Moreover, BLM and WRN colocalized to nuclear foci in three human cell lines. Two regions of WRN that mediate interaction with BLM were identified, and one of these was localized to the exonuclease domain of WRN. Functionally, BLM inhibited the exonuclease activity of WRN. This is the first demonstration of a physical and functional interaction between RecQ helicases. Our observation that RecQ family members interact provides new insights into the complex phenotypic manifestations resulting from the loss of these proteins.
Topics: Adenosine Triphosphatases; Blotting, Western; Cell Line; Cell Nucleus; DNA Helicases; Enzyme-Linked Immunosorbent Assay; Exodeoxyribonucleases; HeLa Cells; Humans; Microscopy, Fluorescence; Models, Biological; Phenotype; Precipitin Tests; Protein Binding; Protein Structure, Tertiary; RecQ Helicases; Recombinant Proteins; Werner Syndrome Helicase
PubMed: 11919194
DOI: 10.1074/jbc.M200914200 -
Frontiers in Endocrinology 2021Bloom syndrome (BS) is a rare autosomal recessive disorder that causes several endocrine abnormalities. So far, only one BS pedigree, without diabetes, has been reported...
Bloom syndrome (BS) is a rare autosomal recessive disorder that causes several endocrine abnormalities. So far, only one BS pedigree, without diabetes, has been reported in the Chinese population. We presented the first case of BS with diabetes in the Chinese population and explored the clinical spectrum associated with endocrine. Possible molecular mechanisms were also investigated. Our study indicated that BS may be one rare cause of diabetes in the Chinese population. We also found a new pathogenic sequence variant in (BLM RecQ like helicase gene)(NM_000057.4) c.692T>G, which may expand the spectrum of variants.
Topics: Bloom Syndrome; Diabetes Mellitus, Type 1; Humans; Male; Mutation; RecQ Helicases; Young Adult
PubMed: 34177791
DOI: 10.3389/fendo.2021.524242 -
Journal of Biochemistry Apr 2001Escherichia coli RecQ helicase is a component of the RecF pathway of recombination whose components are required to reassemble a replisome complex at the site of the... (Review)
Review
Escherichia coli RecQ helicase is a component of the RecF pathway of recombination whose components are required to reassemble a replisome complex at the site of the replication fork after the removal of a lesion. There are at least five RecQ homologues in human cells, including BLM and WRN. The genes encoding BLM and WRN are mutated in the cancer-prone disorder Bloom's syndrome (BS) and the plogeroid disorder Werner's syndrome (WS), respectively. These syndromes are characterized by a high degree of genomic instability, including chromosomal breaks, multiple large deletions, and translocations, and cells derived from BS and WS patients show defects in DNA replication. Recently, it has become clear that a Holliday junction-like structure is formed at stalled replication forks to result in the formation of double-stranded breaks, and recombination plays an important role in the repair of stalled or broken replication forks, leading to the reinitiation of replication. Defects in the processing of stalled replication forks could lead to aberrant recombination events resulting in genetic instability. Recent studies on BLM, WRN, and the RecQ homologue of Saccharomyces cerevisiae, Sgs1, indicate that these RecQ homologues interact with proteins involved in DNA replication, and function in a pathway from the DNA replication check point to homologous recombination.
Topics: Adenosine Triphosphatases; Bacterial Proteins; Bloom Syndrome; DNA Helicases; DNA Replication; Exodeoxyribonucleases; Fungal Proteins; Genome; Humans; Protein Binding; RecQ Helicases; Saccharomyces cerevisiae Proteins; Sister Chromatid Exchange; Werner Syndrome; Werner Syndrome Helicase
PubMed: 11275547
DOI: 10.1093/oxfordjournals.jbchem.a002883 -
The Journal of Biological Chemistry Feb 2001Bloom syndrome and Werner syndrome are genome instability disorders, which result from mutations in two different genes encoding helicases. Both enzymes are members of...
Bloom syndrome and Werner syndrome are genome instability disorders, which result from mutations in two different genes encoding helicases. Both enzymes are members of the RecQ family of helicases, have a 3' --> 5' polarity, and require a 3' single strand tail. In addition to their activity in unwinding duplex substrates, recent studies show that the two enzymes are able to unwind G2 and G4 tetraplexes, prompting speculation that failure to resolve these structures in Bloom syndrome and Werner syndrome cells may contribute to genome instability. The triple helix is another alternate DNA structure that can be formed by sequences that are widely distributed throughout the human genome. Here we show that purified Bloom and Werner helicases can unwind a DNA triple helix. The reactions are dependent on nucleoside triphosphate hydrolysis and require a free 3' tail attached to the third strand. The two enzymes unwound triplexes without requirement for a duplex extension that would form a fork at the junction of the tail and the triplex. In contrast, a duplex formed by the third strand and a complement to the triplex region was a poor substrate for both enzymes. However, the same duplex was readily unwound when a noncomplementary 5' tail was added to form a forked structure. It seems likely that structural features of the triplex mimic those of a fork and thus support efficient unwinding by the two helicases.
Topics: Binding Sites; Bloom Syndrome; DNA; DNA Helicases; Humans; Nucleic Acid Conformation; Nucleic Acid Denaturation; Werner Syndrome
PubMed: 11110789
DOI: 10.1074/jbc.M006784200 -
Molecular Cell Dec 2009Fanconi Anemia (FA) and Bloom's Syndrome (BS) are genetic disorders characterized by overlapping phenotypes, including aberrant DNA repair and cancer predisposition....
Fanconi Anemia (FA) and Bloom's Syndrome (BS) are genetic disorders characterized by overlapping phenotypes, including aberrant DNA repair and cancer predisposition. Here, we show that the FANCM gene product, FANCM protein, links FA and BS by acting as a protein anchor and bridge that targets key components of the FA and BS pathways to stalled replication forks, thus linking multiple components that are necessary for efficient DNA repair. Two highly conserved protein:protein interaction motifs in FANCM, designated MM1 and MM2, were identified. MM1 interacts with the FA core complex by binding to FANCF, whereas MM2 interacts with RM1 and topoisomerase IIIalpha, components of the BS complex. The MM1 and MM2 motifs were independently required to activate the FA and BS pathways. Moreover, a common phenotype of BS and FA cells-an elevated frequency of sister chromatid exchanges-was due to a loss of interaction of the two complexes through FANCM.
Topics: Amino Acid Sequence; Animals; Bloom Syndrome; Cell Line; DNA Damage; DNA Helicases; DNA Repair; DNA Replication; DNA Topoisomerases, Type I; Fanconi Anemia; Genomic Instability; Humans; Multiprotein Complexes; Phenotype; Protein Structure, Tertiary; RNA, Small Interfering; RecQ Helicases; Sister Chromatid Exchange
PubMed: 20064461
DOI: 10.1016/j.molcel.2009.12.006 -
Genetics Nov 1996The Saccharomyces cerevisiae SGS1 gene is homologous to Escherichia coli RecQ and the human BLM and WRN proteins that are defective in the cancer-prone disorder Bloom's...
The Saccharomyces cerevisiae SGS1 gene is homologous to Escherichia coli RecQ and the human BLM and WRN proteins that are defective in the cancer-prone disorder Bloom's syndrome and the premature aging disorder Werner's syndrome, respectively. While recQ mutants are deficient in conjugational recombination and DNA repair, Bloom's syndrome cell lines show hyperrecombination. Bloom's and Werner's syndrome cell lines both exhibit chromosomal instability, sgs1 delta strains show mitotic hyperrecombination, as do Bloom's cells. This was manifested as an increase in the frequency of interchromosomal homologous recombination, intrachromosomal excision recombination, and ectopic recombination. Hyperrecombination was partially independent of both RAD52 and RAD1. Meiotic recombination was not increased in sgs1 delta mutants, although meiosis I chromosome missegregation has been shown to be elevated sgs1 delta suppresses the slow growth of a top3 delta strain lacking topoisomerase III. Although there was an increase in subtelomeric Y' instability in sgs1 delta strains due to hyperrecombination, no evidence was found for an increase in the instability of terminal telomeric sequences in a top3 delta or a sgs1 delta strain. This contrasts with the telomere maintenance defects of Werner's patients. We conclude that the SGS1 gene product is involved in the maintenance of genome stability in S. cerevisiae.
Topics: Adenosine Triphosphatases; Alleles; Bloom Syndrome; Chromosomes, Fungal; DNA Helicases; DNA Topoisomerases, Type I; Diploidy; Genome, Fungal; Humans; Mitosis; Phenotype; RecQ Helicases; Recombination, Genetic; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Spores, Fungal; Telomere; Werner Syndrome
PubMed: 8913739
DOI: 10.1093/genetics/144.3.935 -
Cell Cycle (Georgetown, Tex.) Mar 2013
Topics: DNA Helicases; DNA Repair; Enzyme Inhibitors; Humans; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; RecQ Helicases; Small Molecule Libraries
PubMed: 23422862
DOI: 10.4161/cc.23953