The BLM Helicase: Keeping recombination honest?

Her, Joonyoung; Ray, Chandni; Bunting, Samuel F.

doi:10.1080/15384101.2017.1421045

Cited by 2 publications

(4 citation statements)

References 7 publications

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“…Conversely, BLM overexpression reduces RAD51 focus formation (69). These findings are consistent with a model where BLM prevents RAD51 filament from being made in BRCA1-deficient cells (69,74). However, the exact molecular mechanism underlying these observations remains unknown (69,74).…”

Section: Discussionsupporting

confidence: 91%

“…These findings are consistent with a model where BLM prevents RAD51 filament from being made in BRCA1-deficient cells (69,74). However, the exact molecular mechanism underlying these observations remains unknown (69,74). If BLM really removes RAD51 from ssDNA in cells, then one would need to invoke a model in which the in vivo activity of BLM is markedly different from its in vitro characteristics.…”

Section: Discussionsupporting

confidence: 91%

“…As such, it is possible that RAD51 foci measurements do not reflect the earliest and latest stages of recombination when RAD51 may be unstable and undergoing substantial turnover, but may instead only reflect the most stable intermediates that exist after presynaptic complex assembly and perhaps the earliest stages of strand invasion. Interestingly, a recent study has shown that RAD51 focus formation is regulated by BLM (69,74). Cells lacking BRCA1 show decreased RAD51 foci formation upon exposure to ionizing radiation, but deletion of BLM restores RAD51 focus formation in these BRCA1-deficient cells (69).…”

Section: Discussionmentioning

confidence: 99%

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Single-molecule visualization of human BLM helicase as it acts upon double- and single-stranded DNA substrates

Xue

Daley

Xue

et al. 2019

Nucleic Acids Research

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Bloom helicase (BLM) and its orthologs are essential for the maintenance of genome integrity. BLM defects represent the underlying cause of Bloom Syndrome, a rare genetic disorder that is marked by strong cancer predisposition. BLM deficient cells accumulate extensive chromosomal aberrations stemming from dysfunctions in homologous recombination (HR). BLM participates in several HR stages and helps dismantle potentially harmful HR intermediates. However, much remains to be learned about the molecular mechanisms of these BLM-mediated regulatory effects. Here, we use DNA curtains to directly visualize the activity of BLM helicase on single molecules of DNA. Our data show that BLM is a robust helicase capable of rapidly (∼70–80 base pairs per second) unwinding extensive tracts (∼8–10 kilobases) of double-stranded DNA (dsDNA). Importantly, we find no evidence for BLM activity on single-stranded DNA (ssDNA) that is bound by replication protein A (RPA). Likewise, our results show that BLM can neither associate with nor translocate on ssDNA that is bound by the recombinase protein RAD51. Moreover, our data reveal that the presence of RAD51 also blocks BLM translocation on dsDNA substrates. We discuss our findings within the context of potential regulator roles for BLM helicase during DNA replication and repair.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Single-molecule visualization of human BLM helicase as it acts upon double- and single-stranded DNA substrates

Xue

Daley

Xue

et al. 2019

Nucleic Acids Research

View full text Add to dashboard Cite

show abstract

“…Biochemical studies showed that the deletion of BLM enhances the assembly of RAD51 at the ssDNA break site, while overexpression of BLM disrupts the RAD51 assembly through its helicase activity 108 , 109 . Therefore, BLM works as a ‘anti-recombinase’ at early and late stages of HR by: (i) preventing HR by disrupting the RAD51 assembly on the ssDNA of DSBs to make sure that HR only occurs between sequences with high homology; and (ii) preventing SCEs by separating the repaired DNA from the template DNA strand that arises at the final stages of HR 110 , 111 .…”

Section: Resultsmentioning

confidence: 99%

Investigating the pathogenic SNPs in BLM helicase and their biological consequences by computational approach

Alzahrani

Ahmed

Sharma

et al. 2020

Sci Rep

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The BLM helicase protein plays a vital role in DNA replication and the maintenance of genomic integrity. Variation in the BLM helicase gene resulted in defects in the DNA repair mechanism and was reported to be associated with Bloom syndrome (BS) and cancer. Despite extensive investigation of helicase proteins in humans, no attempt has previously been made to comprehensively analyse the single nucleotide polymorphism (SNPs) of the BLM gene. In this study, a comprehensive analysis of SNPs on the BLM gene was performed to identify, characterize and validate the pathogenic SNPs using computational approaches. We obtained SNP data from the dbSNP database version 150 and mapped these data to the genomic coordinates of the “NM_000057.3” transcript expressing BLM helicase (P54132). There were 607 SNPs mapped to missense, 29 SNPs mapped to nonsense, and 19 SNPs mapped to 3′-UTR regions. Initially, we used many consensus tools of SIFT, PROVEAN, Condel, and PolyPhen-2, which together increased the accuracy of prediction and identified 18 highly pathogenic non-synonymous SNPs (nsSNPs) out of 607 SNPs. Subsequently, these 18 high-confidence pathogenic nsSNPs were analysed for BLM protein stability, structure–function relationships and disease associations using various bioinformatics tools. These 18 mutants of the BLM protein along with the native protein were further investigated using molecular dynamics simulations to examine the structural consequences of the mutations, which might reveal their malfunction and contribution to disease. In addition, 28 SNPs were predicted as “stop gained” nonsense SNPs and one SNP was predicted as “start lost”. Two SNPs in the 3′UTR were found to abolish miRNA binding and thus may enhance the expression of BLM. Interestingly, we found that BLM mRNA overexpression is associated with different types of cancers. Further investigation showed that the dysregulation of BLM is associated with poor overall survival (OS) for lung and gastric cancer patients and hence led to the conclusion that BLM has the potential to be used as an important prognostic marker for the detection of lung and gastric cancer.

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The BLM Helicase: Keeping recombination honest?

Cited by 2 publications

References 7 publications

Single-molecule visualization of human BLM helicase as it acts upon double- and single-stranded DNA substrates

Single-molecule visualization of human BLM helicase as it acts upon double- and single-stranded DNA substrates

Investigating the pathogenic SNPs in BLM helicase and their biological consequences by computational approach

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