scholarly journals Role of the Bloom's syndrome helicase in maintenance of genome stability

2001 ◽  
Vol 29 (2) ◽  
pp. 201-204 ◽  
Author(s):  
I. D. Hickson ◽  
S. L. Davies ◽  
J.-L. Li ◽  
N. C. Levitt ◽  
P. Mohaghegh ◽  
...  
Keyword(s):  
Genomic Instability ◽  
Genome Stability ◽  
Family Members ◽  
Genome Integrity ◽  
Bloom's Syndrome ◽  
Dna Helicases ◽  
Werner's Syndrome ◽  
Bloom’S Syndrome ◽  
Rothmund Thomson Syndrome

The RecQ family of DNA helicases has members in all organisms analysed. In humans, defects in three family members are associated with disease conditions: BLM is defective in Bloom's syndrome, WRN in Werner's syndrome and RTS in Rothmund-Thomson syndrome. In each case, cells from affected individuals show inherent genomic instability. The focus of our work is the Bloom's syndrome gene and its product, BLM. Here, we review the latest information concerning the roles of BLM in the maintenance of genome integrity.

scholarly journals Roles of the Bloom's syndrome helicase in the maintenance of genome stability

2005 ◽  
Vol 33 (6) ◽  
pp. 1456-1459 ◽  
Author(s):  
C.F. Cheok ◽  
C.Z. Bachrati ◽  
K.L. Chan ◽  
C. Ralf ◽  
L. Wu ◽  
...  
Keyword(s):  
Genome Stability ◽  
Protein A ◽  
Sister Chromatid Exchanges ◽  
Premature Aging ◽  
Bloom's Syndrome ◽  
Dna Helicases ◽  
Bloom’S Syndrome ◽  
Recombination Repair ◽  
Rothmund Thomson Syndrome ◽  
Chromatid Exchanges

The RecQ family of DNA helicases is highly conserved in evolution from bacteria to humans. Of the five known human RecQ family members, three (BLM, WRN and RECQ4, which cause Bloom's syndrome, Werner's syndrome and Rothmund–Thomson syndrome respectively) are mutated in distinct clinical disorders associated with cancer predisposition and/or premature aging. BLM forms part of a multienzyme complex including topoisomerase IIIα, replication protein A and a newly identified factor called BLAP75. Together, these proteins play a role in the resolution of DNA structures that arise during the process of homologous recombination repair. In the absence of BLM, cells show genomic instability and a high incidence of sister-chromatid exchanges. In addition to a DNA structure-specific helicase activity, BLM also catalyses Holliday-junction branch migration and the annealing of complementary single-stranded DNA molecules.

scholarly journals SGS1, a Homologue of the Bloom's and Werner's Syndrome Genes, Is Required for Maintenance of Genome Stability in Saccharomyces cerevisiae

Genetics ◽  
1996 ◽  
Vol 144 (3) ◽  
pp. 935-945 ◽  
Author(s):  
Paul M Watt ◽  
Ian D Hickson ◽  
Rhona H Borts ◽  
Edward J Louis
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Cell Lines ◽  
Genome Stability ◽  
Premature Aging ◽  
Telomere Maintenance ◽  
Bloom's Syndrome ◽  
Telomeric Sequences ◽  
Werner’S Syndrome ◽  
Werner's Syndrome ◽  
Bloom’S Syndrome

Abstract 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. sgslΔ 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 sgs1Δ mutants, although meiosis I chromosome missegregation has been shown to be elevated. sgs1Δ suppresses the slow growth of a top3Δ strain lacking topoisomerase 111. Although there was an increase in subtelomeric Y' instability in sgs1Δ strains due to hyperrecombination, no evidence was found for an increase in the instability of terminal telomeric sequences in a top3Δ or a sgs1Δ 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. cermisiae.

Genomic instability and cancer: lessons from analysis of Bloom's syndrome

2009 ◽  
Vol 37 (3) ◽  
pp. 553-559 ◽  
Author(s):  
Miranda Payne ◽  
Ian D. Hickson
Keyword(s):  
Genomic Instability ◽  
Mitotic Chromosome ◽  
Genetic Defect ◽  
Autosomal Recessive Disorder ◽  
Recq Helicase ◽  
Bloom's Syndrome ◽  
Binding Partners ◽  
Bloom’S Syndrome ◽  
Syndrome Protein ◽  
Blm Gene

Bloom's syndrome (BS) is a rare autosomal recessive disorder characterized by genomic instability and cancer predisposition. The underlying genetic defect is mutation of the BLM gene, producing deficiency in the RecQ helicase BLM (Bloom's syndrome protein). The present article begins by introducing BLM and its binding partners before reviewing its known biochemical activities and its potential roles both as a pro-recombinase and as a suppressor of homologous recombination. Finally, the evidence for an emerging role in mitotic chromosome segregation is examined.

scholarly journals Ku80 is involved in telomere maintenance but dispensable for genomic stability in Leishmania mexicana

2021 ◽  
Vol 15 (12) ◽  
pp. e0010041
Author(s):  
Ester Poláková ◽  
Amanda T. S. Albanaz ◽  
Alexandra Zakharova ◽  
Tatiana S. Novozhilova ◽  
Evgeny S. Gerasimov ◽  
...  
Keyword(s):  
Genome Stability ◽  
Southern Blotting ◽  
Telomere Maintenance ◽  
Genome Integrity ◽  
Whole Genome ◽  
Leishmania Mexicana ◽  
Telomere Elongation ◽  
Ku Proteins ◽  
Telomere Lengthening

Background Telomeres are indispensable for genome stability maintenance. They are maintained by the telomere-associated protein complex, which include Ku proteins and a telomerase among others. Here, we investigated a role of Ku80 in Leishmania mexicana. Leishmania is a genus of parasitic protists of the family Trypanosomatidae causing a vector-born disease called leishmaniasis. Methodology/Principal findings We used the previously established CRISPR/Cas9 system to mediate ablation of Ku80- and Ku70-encoding genes in L. mexicana. Complete knock-outs of both genes were confirmed by Southern blotting, whole-genome Illumina sequencing, and RT-qPCR. Resulting telomeric phenotypes were subsequently investigated using Southern blotting detection of terminal restriction fragments. The genome integrity in the Ku80- deficient cells was further investigated by whole-genome sequencing. Our work revealed that telomeres in the ΔKu80 L. mexicana are elongated compared to those of the wild type. This is a surprising finding considering that in another model trypanosomatid, Trypanosoma brucei, they are shortened upon ablation of the same gene. A telomere elongation phenotype has been documented in other species and associated with a presence of telomerase-independent alternative telomere lengthening pathway. Our results also showed that Ku80 appears to be not involved in genome stability maintenance in L. mexicana. Conclusion/Significance Ablation of the Ku proteins in L. mexicana triggers telomere elongation, but does not have an adverse impact on genome integrity.

scholarly journals Phosphorylation of the Bloom's Syndrome Helicase and Its Role in Recovery from S-Phase Arrest

2004 ◽  
Vol 24 (3) ◽  
pp. 1279-1291 ◽  
Author(s):  
Sally L. Davies ◽  
Phillip S. North ◽  
Alwyn Dart ◽  
Nicholas D. Lakin ◽  
Ian D. Hickson
Keyword(s):  
Dna Replication ◽  
Genome Stability ◽  
Genetic Disorder ◽  
S Phase ◽  
Recq Helicase ◽  
Bloom's Syndrome ◽  
Recq Helicases ◽  
Phase Arrest ◽  
Bloom’S Syndrome ◽  
S Phase Arrest

ABSTRACT Bloom's syndrome (BS) is a human genetic disorder associated with cancer predisposition. The BS gene product, BLM, is a member of the RecQ helicase family, which is required for the maintenance of genome stability in all organisms. In budding and fission yeasts, loss of RecQ helicase function confers sensitivity to inhibitors of DNA replication, such as hydroxyurea (HU), by failure to execute normal cell cycle progression following recovery from such an S-phase arrest. We have examined the role of the human BLM protein in recovery from S-phase arrest mediated by HU and have probed whether the stress-activated ATR kinase, which functions in checkpoint signaling during S-phase arrest, plays a role in the regulation of BLM function. We show that, consistent with a role for BLM in protection of human cells against the toxicity associated with arrest of DNA replication, BS cells are hypersensitive to HU. BLM physically associates with ATR (ataxia telangiectasia and rad3+ related) protein and is phosphorylated on two residues in the N-terminal domain, Thr-99 and Thr-122, by this kinase. Moreover, BS cells ectopically expressing a BLM protein containing phosphorylation-resistant T99A/T122A substitutions fail to adequately recover from an HU-induced replication blockade, and the cells subsequently arrest at a caffeine-sensitive G2/M checkpoint. These abnormalities are not associated with a failure of the BLM-T99A/T122A protein to localize to replication foci or to colocalize either with ATR itself or with other proteins that are required for response to DNA damage, such as phosphorylated histone H2AX and RAD51. Our data indicate that RecQ helicases play a conserved role in recovery from perturbations in DNA replication and are consistent with a model in which RecQ helicases act to restore productive DNA replication following S-phase arrest and hence prevent subsequent genomic instability.

scholarly journals N6-Methyladenosine, DNA Repair, and Genome Stability

2021 ◽  
Vol 8 ◽  
Author(s):  
Fei Qu ◽  
Pawlos S. Tsegay ◽  
Yuan Liu
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Cellular Response ◽  
Genome Stability ◽  
Fine Tuning ◽  
Genome Integrity ◽  
Cell Renewal ◽  
The Novel ◽  
Cellular Sensitivity

N6-methyladenosine (m6A) modification in mRNAs and non-coding RNAs is a newly identified epitranscriptomic mark. It provides a fine-tuning of gene expression to serve as a cellular response to endogenous and exogenous stimuli. m6A is involved in regulating genes in multiple cellular pathways and functions, including circadian rhythm, cell renewal, differentiation, neurogenesis, immunity, among others. Disruption of m6A regulation is associated with cancer, obesity, and immune diseases. Recent studies have shown that m6A can be induced by oxidative stress and DNA damage to regulate DNA repair. Also, deficiency of the m6A eraser, fat mass obesity-associated protein (FTO) can increase cellular sensitivity to genotoxicants. These findings shed light on the novel roles of m6A in modulating DNA repair and genome integrity and stability through responding to DNA damage. In this mini-review, we discuss recent progress in the understanding of a unique role of m6As in mRNAs, lncRNAs, and microRNAs in DNA damage response and regulation of DNA repair and genome integrity and instability.

scholarly journals BLAP75, an essential component of Bloom's syndrome protein complexes that maintain genome integrity

2005 ◽  
Vol 24 (7) ◽  
pp. 1465-1476 ◽  
Author(s):  
Jinhu Yin ◽  
Alexandra Sobeck ◽  
Chang Xu ◽  
Amom Ruhikanta Meetei ◽  
Maureen Hoatlin ◽  
...  
Keyword(s):  
Protein Complexes ◽  
Genome Integrity ◽  
Bloom's Syndrome ◽  
Essential Component ◽  
Bloom’S Syndrome ◽  
Syndrome Protein
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