The SMX DNA Repair Tri-nuclease

Wyatt, Haley D.M.; Laister, Rob C.; Martin, Stephen R.; Arrowsmith, C.H.; West, Stephen C.

doi:10.1016/j.molcel.2017.01.031

Cited by 105 publications

(155 citation statements)

References 61 publications

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“…168 We have found that S. cerevisiae SSEs Mus81, Rad1-Rad10, and Slx1-Slx4 are all important in causing fragility at the Flex1 structure-forming subregion of FRA16D. 36 The involvement of all of these components suggests that they are functioning in a SSE super complex as has been shown for the human complex in vitro 169 , and that one important target of SSEs at CFSs in human cells is forks stalled at DNA structures.…”

Section: Cleavage At Secondary Structures Within Cfss Is a Cause Ofmentioning

confidence: 82%

The role of fork stalling and DNA structures in causing chromosome fragility

Kaushal

Freudenreich

2019

Genes Chromosomes & Cancer

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Alternative non‐B form DNA structures, also called secondary structures, can form in certain DNA sequences under conditions that produce single‐stranded DNA, such as during replication, transcription, and repair. Direct links between secondary structure formation, replication fork stalling, and genomic instability have been found for many repeated DNA sequences that cause disease when they expand. Common fragile sites (CFSs) are known to be AT‐rich and break under replication stress, yet the molecular basis for their fragility is still being investigated. Over the past several years, new evidence has linked both the formation of secondary structures and transcription to fork stalling and fragility of CFSs. How these two events may synergize to cause fragility and the role of nuclease cleavage at secondary structures in rare and CFSs are discussed here. We also highlight evidence for a new hypothesis that secondary structures at CFSs not only initiate fragility but also inhibit healing, resulting in their characteristic appearance.

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Section: Cleavage At Secondary Structures Within Cfss Is a Cause Ofmentioning

confidence: 82%

The role of fork stalling and DNA structures in causing chromosome fragility

Kaushal

Freudenreich

2019

Genes Chromosomes & Cancer

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“…Interestingly, deletion of the SLX4-interacting region of MUS81 broadens substrate specificity, allowing the complex to target much more easily also replication intermediates at perturbed forks (46). Serine 87 is within the region interacting with SLX4 and its phosphorylation makes MUS81 more prone to associate with SLX4, providing a mechanistic explanation to the unscheduled targeting by the MUS81 S87D protein of HJ-like and possibly other branched intermediates during replication.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation by CK2 Regulates MUS81/EME1 in Mitosis and After Replication Stress

Palma

Pugliese

Murfuni

et al. 2018

Preprint

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The MUS81 complex is crucial for preserving genome stability through the resolution of branched DNA intermediates in mitosis. However, untimely activation of the MUS81 complex in S-phase is dangerous. Little is known about the regulation of the human MUS81 complex and how deregulated activation affects chromosome integrity. Here, we show that the CK2 kinase phosphorylates MUS81 at Serine 87 in late-G2/mitosis, and upon mild replication stress. Phosphorylated MUS81 interacts with SLX4, and this association promotes the function of the MUS81 complex. In line with a role in mitosis, phosphorylation at Serine 87 is suppressed in S-phase and is mainly detected in the MUS81 molecules associated with EME1. Loss of CK2-dependent MUS81 phosphorylation contributes modestly to chromosome integrity, however, expression of the phosphomimic form induces DSBs accumulation in S-phase, because of unscheduled targeting of HJ-like DNA intermediates, and generates a wide chromosome instability phenotype. Collectively, our findings describe a novel regulatory mechanism controlling the MUS81 complex function in human cells.Furthermore, they indicate that, genome stability depends mainly on the ability of cells to counteract targeting of branched intermediates by the MUS81/EME1 complex in S-phase, rather than on a correct MUS81 function in mitosis.

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“…single HJs and D-loop structures), are processed by a second mechanism which involves structure-selective endonuclease (SSE)-mediated resolution [31,32,39,40]. There are two genetically distinct resolution pathways: one is mediated by the SLX1–SLX4, MUS81-EME1 and XPF-ERCC1 (SMX) tri-nuclease complex [27,31,41–46], and the other is mediated by GEN1 endonuclease [47–50]. …”

Section: The Origin Of Hr-ufbsmentioning

confidence: 99%

A new class of ultrafine anaphase bridges generated by homologous recombination

Chan

West

2018

Cell Cycle

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Ultrafine anaphase bridges (UFBs) are a potential source of genome instability that is a hallmark of cancer. UFBs can arise from DNA catenanes at centromeres/rDNA loci, late replication intermediates induced by replication stress, and DNA linkages at telomeres. Recently, it was reported that DNA intertwinements generated by homologous recombination give rise to a new class of UFBs, which have been termed homologous recombination ultrafine bridges (HR-UFBs). HR-UFBs are decorated with PICH and BLM in anaphase, and are subsequently converted to RPA-coated, single-stranded DNA bridges. Breakage of these sister chromatid entanglements leads to DNA damage that can be repaired by non-homologous end joining in the next cell cycle, but the potential consequences include DNA rearrangements, chromosome translocations and fusions. Visualisation of these HR-UFBs, and knowledge of how they arise, provides a molecular basis to explain how upregulation of homologous recombination or failure to resolve recombination intermediates leads to the development of chromosomal instability observed in certain cancers.

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The SMX DNA Repair Tri-nuclease

Cited by 105 publications

References 61 publications

The role of fork stalling and DNA structures in causing chromosome fragility

The role of fork stalling and DNA structures in causing chromosome fragility

Phosphorylation by CK2 Regulates MUS81/EME1 in Mitosis and After Replication Stress

A new class of ultrafine anaphase bridges generated by homologous recombination

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