SLX4: multitasking to maintain genome stability

Guervilly, Jean-Hugues; Gaillard, Patrick

doi:10.1080/10409238.2018.1488803

Cited by 37 publications

(40 citation statements)

References 233 publications

(542 reference statements)

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“…Notably, cells synchronized in G1/S phase contain a pool of MUS81-EME1 that does not cofractionate with the rest of the complex on a sucrose gradient (Wyatt et al., 2017), suggesting the existence of functional subcomplexes. In addition to being able to cleave recombination-associated Holliday junctions, SLX4 has also been reported to promote endonucleolytic processing of replication forks (for review see Guervilly and Gaillard, 2018). Although this seems to primarily involve MUS81-EME1 and SLX1, SLX4-promoted fork processing by XPF-ERCC1 was recently reported (Bétous et al., 2018).…”

Section: Resultsmentioning

confidence: 99%

WRNIP1 Protects Reversed DNA Replication Forks from SLX4-Dependent Nucleolytic Cleavage

et al. 2019

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SummaryDuring DNA replication stress, stalled replication forks need to be stabilized to prevent fork collapse and genome instability. The AAA + ATPase WRNIP1 (Werner Helicase Interacting Protein 1) has been implicated in the protection of stalled replication forks from nucleolytic degradation, but the underlying molecular mechanism has remained unclear. Here we show that WRNIP1 exerts its protective function downstream of fork reversal. Unexpectedly though, WRNIP1 is not part of the well-studied BRCA2-dependent branch of fork protection but seems to protect the junction point of reversed replication forks from SLX4-mediated endonucleolytic degradation, possibly by directly binding to reversed replication forks. This function is specific to the shorter, less abundant, and less conserved variant of WRNIP1. Overall, our data suggest that in the absence of BRCA2 and WRNIP1 different DNA substrates are generated at reversed forks but that nascent strand degradation in both cases depends on the activity of exonucleases and structure-specific endonucleases.

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Section: Resultsmentioning

confidence: 99%

WRNIP1 Protects Reversed DNA Replication Forks from SLX4-Dependent Nucleolytic Cleavage

et al. 2019

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“…Another structure-selective DNA nuclease, the Slx1-Slx4 complex, also contributes to RI removal. The mammalian SLX4 harbors additional domains for binding to MUS81-EME1 and other proteins, gaining additional functions and regulation, which has been nicely summarized in a recent review (Guervilly and Gaillard 2018).…”

Section: Sumoylation Collaborates With Phosphorylation To Regulate Hjmentioning

confidence: 99%

Intricate SUMO-based control of the homologous recombination machinery

Dhingra

Zhao

2019

Genes Dev.

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The homologous recombination (HR) machinery plays multiple roles in genome maintenance. Best studied in the context of DNA double-stranded break (DSB) repair, recombination enzymes can cleave, pair, and unwind DNA molecules, and collaborate with regulatory proteins to execute multiple DNA processing steps before generating specific repair products. HR proteins also help to cope with problems arising from DNA replication, modulating impaired replication forks or filling DNA gaps. Given these important roles, it is not surprising that each HR step is subject to complex regulation to adjust repair efficiency and outcomes as well as to limit toxic intermediates. Recent studies have revealed intricate regulation of all steps of HR by the protein modifier SUMO, which has been increasingly recognized for its broad influence in nuclear functions. This review aims to connect established roles of SUMO with its newly identified effects on recombinational repair and stimulate further thought on many unanswered questions.Homologous recombination is critical for several aspects of life, ranging from DNA repair and genome duplication to gamete production. Our understanding of HR pathways has benefited from a combination of assay systems. In cells, the generation of a defined DSB allows quantitative assessment of the status of the broken DNA molecules and the repair proteins at a temporal resolution, as well as determination of the genetic requirement for each step of repair (Haber 2016). Extensive biochemical analyses and more recently single molecule experiments have further defined the activities of HR enzymes and elucidated how they can collaborate in multiple HR steps. Several recent reviews have discussed these findings in detail (Symington et al. 2014;Heyer 2015;Ranjha et al. 2018); thus, we give only a brief overview here for each HR step to provide the context of SUMO-based regulation. As the HR machinery and its sumoylation are best examined in budding yeast, we use this system as an index for summarizing SUMO-based control. We also discuss additional regulation in mammalian cells and highlight their similarities and differences with those found in yeast. It is noteworthy that SUMO plays important roles in modulating protein recruitment to damaged chromatin and in other DNA break repair pathways. As these topics have been well covered in other reviews (Schwertman et al. 2016; Garvin and Morris 2017), they are not addressed here in order to maintain the focus on the regulation of core HR machinery.

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“…In both yeast and humans, DNA damage signaling kinases phosphorylate proteins in homologous recombination (HR)‐directed repair and have been shown to play an important regulatory role. For example, Mec1 phosphorylates Rtt107, Slx4, and Sgs1, all of which are known to play multiple roles in HR‐mediated repair, from the control of resection to the dissolution or resolution of joint chromosome structures (Sarbajna & West, ; Hang & Zhao, ; Cussiol et al , ; Guervilly & Gaillard, ). Recent work from our laboratory has revealed that phosphorylation of these proteins correlates with the ability of cells to suppress GCRs, suggesting that proper control of HR repair is essential for preventing chromosomal rearrangements (Lanz et al , ).…”

Section: Introductionmentioning

confidence: 99%

DNA damage kinase signaling: checkpoint and repair at 30 years

2019

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From bacteria to mammalian cells, damaged DNA is sensed and targeted by DNA repair pathways. In eukaryotes, kinases play a central role in coordinating the DNA damage response. DNA damage signaling kinases were identified over two decades ago and linked to the cell cycle checkpoint concept proposed by Weinert and Hartwell in 1988. Connections between the DNA damage signaling kinases and DNA repair were scant at first, and the initial perception was that the importance of these kinases for genome integrity was largely an indirect effect of their roles in checkpoints, DNA replication, and transcription. As more substrates of DNA damage signaling kinases were identified, it became clear that they directly regulate a wide range of DNA repair factors. Here, we review our current understanding of DNA damage signaling kinases, delineating the key substrates in budding yeast and humans. We trace the progress of the field in the last 30 years and discuss our current understanding of the major substrate regulatory mechanisms involved in checkpoint responses and DNA repair.

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SLX4: multitasking to maintain genome stability

Cited by 37 publications

References 233 publications

WRNIP1 Protects Reversed DNA Replication Forks from SLX4-Dependent Nucleolytic Cleavage

WRNIP1 Protects Reversed DNA Replication Forks from SLX4-Dependent Nucleolytic Cleavage

Intricate SUMO-based control of the homologous recombination machinery

DNA damage kinase signaling: checkpoint and repair at 30 years

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