Structural mechanisms of human RecQ helicases WRN and BLM

Kitano, Katsuhisa

doi:10.3389/fgene.2014.00366

Cited by 64 publications

(63 citation statements)

References 74 publications

(170 reference statements)

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“…S8). These findings raise the possibility that the HRDC-motor core interaction stabilizes the helicase in a configuration specific for invasion disruption (36) (Fig. 4B).…”

Section: Discussionmentioning

confidence: 85%

Shuttling along DNA and directed processing of D-loops by RecQ helicase support quality control of homologous recombination

Harami

Seol

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Cells must continuously repair inevitable DNA damage while avoiding the deleterious consequences of imprecise repair. Distinction between legitimate and illegitimate repair processes is thought to be achieved in part through differential recognition and processing of specific noncanonical DNA structures, although the mechanistic basis of discrimination remains poorly defined. Here, we show that Escherichia coli RecQ, a central DNA recombination and repair enzyme, exhibits differential processing of DNA substrates based on their geometry and structure. Through single-molecule and ensemble biophysical experiments, we elucidate how the conserved domain architecture of RecQ supports geometry-dependent shuttling and directed processing of recombination-intermediate [displacement loop (D-loop)] substrates. Our study shows that these activities together suppress illegitimate recombination in vivo, whereas unregulated duplex unwinding is detrimental for recombination precision. Based on these results, we propose a mechanism through which RecQ helicases achieve recombination precision and efficiency.RecQ | helicase | magnetic tweezers | single molecule | DNA unwinding

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“…S8). These findings raise the possibility that the HRDC-motor core interaction stabilizes the helicase in a configuration specific for invasion disruption (36) (Fig. 4B).…”

Section: Discussionmentioning

confidence: 85%

Shuttling along DNA and directed processing of D-loops by RecQ helicase support quality control of homologous recombination

Harami

Seol

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Although the WRN and the BLM helicases belong both to the family of RecQ helicases, defects of either during DSB response may lead to opposing outcomes [Suhasini and Brosh, 2013;Croteau et al, 2014;Keijzers et al, 2014;Kitano, 2014]. Loss of WRN is associated with a variegated translocation mosaicism and a reduction in DNA recombination [Salk et al, 1981;Dhillon et al, 2007;Melcher et al, 2000].…”

Section: Genes and Proteinsmentioning

confidence: 99%

Mechanisms of Origin, Phenotypic Effects and Diagnostic Implications of Complex Chromosome Rearrangements

Poot

Haaf

2015

Mol Syndromol

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Complex chromosome rearrangements (CCRs) are currently defined as structural genome variations that involve more than 2 chromosome breaks and result in exchanges of chromosomal segments. They are thought to be extremely rare, but their detection rate is rising because of improvements in molecular cytogenetic technology. Their population frequency is also underestimated, since many CCRs may not elicit a phenotypic effect. CCRs may be the result of fork stalling and template switching, microhomology-mediated break-induced repair, breakage-fusion-bridge cycles, or chromothripsis. Patients with chromosomal instability syndromes show elevated rates of CCRs due to impaired DNA double-strand break responses during meiosis. Therefore, the putative functions of the proteins encoded by ATM, BLM, WRN, ATR, MRE11, NBS1, and RAD51 in preventing CCRs are discussed. CCRs may exert a pathogenic effect by either (1) gene dosage-dependent mechanisms, e.g. haploinsufficiency, (2) mechanisms based on disruption of the genomic architecture, such that genes, parts of genes or regulatory elements are truncated, fused or relocated and thus their interactions disturbed - these mechanisms will predominantly affect gene expression - or (3) mixed mutation mechanisms in which a CCR on one chromosome is combined with a different type of mutation on the other chromosome. Such inferred mechanisms of pathogenicity need corroboration by mRNA sequencing. Also, future studies with in vitro models, such as inducible pluripotent stem cells from patients with CCRs, and transgenic model organisms should substantiate current inferences regarding putative pathogenic effects of CCRs. The ramifications of the growing body of information on CCRs for clinical and experimental genetics and future treatment modalities are briefly illustrated with 2 cases, one of which suggests KDM4C(JMJD2C) as a novel candidate gene for mental retardation.

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“…Our results demonstrate that the HRDC domain also plays a critical role in strand synthesis across the telomeric G-rich repeats in vitro and contributes to telomere length homeostasis in vivo. The HRDC domain is conserved among many RecQ helicases and is thought to mediate protein interactions and DNA binding (5). Interestingly, a recent study has shown that the HRDC domain of BLM interacts with the single-stranded DNA ahead of G4 DNA and cooperates with helicase activity to unwind these DNA structures (60).…”

Section: Discussionmentioning

confidence: 99%

The Werner Syndrome Helicase Coordinates Sequential Strand Displacement and FEN1-Mediated Flap Cleavage during Polymerase δ Elongation

Reddy

Comai

2017

Molecular and Cellular Biology

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The Werner syndrome protein (WRN) suppresses the loss of telomeres replicated by lagging-strand synthesis by a yet to be defined mechanism. Here, we show that whereas either WRN or the Bloom syndrome helicase (BLM) stimulates DNA polymerase ␦ progression across telomeric G-rich repeats, only WRN promotes sequential strand displacement synthesis and FEN1 cleavage, a critical step in Okazaki fragment maturation, at these sequences. Helicase activity, as well as the conserved winged-helix (WH) motif and the helicase and RNase D C-terminal (HRDC) domain play important but distinct roles in this process. Remarkably, WRN also influences the formation of FEN1 cleavage products during strand displacement on a nontelomeric substrate, suggesting that WRN recruitment and cooperative interaction with FEN1 during lagging-strand synthesis may serve to regulate sequential strand displacement and flap cleavage at other genomic sites. These findings define a biochemical context for the physiological role of WRN in maintaining genetic stability.

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Structural mechanisms of human RecQ helicases WRN and BLM

Cited by 64 publications

References 74 publications

Shuttling along DNA and directed processing of D-loops by RecQ helicase support quality control of homologous recombination

Shuttling along DNA and directed processing of D-loops by RecQ helicase support quality control of homologous recombination

Mechanisms of Origin, Phenotypic Effects and Diagnostic Implications of Complex Chromosome Rearrangements

The Werner Syndrome Helicase Coordinates Sequential Strand Displacement and FEN1-Mediated Flap Cleavage during Polymerase δ Elongation

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