Holliday junction processing enzymes as guardians of genome stability

Sarbajna, Shriparna; West, Stephen C.

doi:10.1016/j.tibs.2014.07.003

Cited by 92 publications

(81 citation statements)

References 86 publications

(175 reference statements)

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“…In some cases, the recombination intermediates are converted into a 'double Holliday junction' and subsequently resolved by Holliday junction resolvases (e.g., GEN1 or the SLX4 complex) (Garner et al 2013, Wyatt et al 2013) (with or without crossover) or the BLM helicase complex (without crossover) (Wu & Hickson 2003). For more complete discussion of HR mechanisms such as their relationship with competing NHEJ (the pathway choice) or Holliday junction resolvases, readers should refer to the recent excellent reviews (Chapman et al 2012, Sarbajna & West 2014.…”

Section: Basic Molecular Mechanisms Of Hr Repairmentioning

confidence: 99%

Defects in homologous recombination repair behind the human diseases: FA and HBOC

Katsuki

Takata

2016

Endocrine-Related Cancer

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Hereditary breast and ovarian cancer (HBOC) syndrome and a rare childhood disorder Fanconi anemia (FA) are caused by homologous recombination (HR) defects, and some of the causative genes overlap. Recent studies in this field have led to the exciting development of PARP inhibitors as novel cancer therapeutics and have clarified important mechanisms underlying genome instability and tumor suppression in HR-defective disorders. In this review, we provide an overview of the basic molecular mechanisms governing HR and DNA crosslink repair, highlighting BRCA2, and the intriguing relationship between HBOC and FA.

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Section: Basic Molecular Mechanisms Of Hr Repairmentioning

confidence: 99%

Defects in homologous recombination repair behind the human diseases: FA and HBOC

Katsuki

Takata

2016

Endocrine-Related Cancer

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“…Replication forks typically bypass MMS-induced replication blocks via template switching mechanisms, resulting in physical linkages between sister chromatids, also known as joint molecules (JMs) (Branzei et al 2008). Processing of these linkages is crucial for chromosome segregation and occurs mainly through two parallel mechanisms, either dissolution via the Sgs1-Top3-Rmi1 complex or resolution via the Mus81-Mms4 structure-specific endonuclease (Hickson and Mankouri 2011;Sarbajna and West 2014). The Mus81-Mms4 pathway is under strict cell cycle regulation, being activated in G 2 /M by action of the CDK and Cdc5 kinases and presumably antagonized by DDC-mediated cell cycle arrest (Zhang et al 2009;Szakal and Branzei 2013).…”

Section: Pph3 and Slx4 Represent Complementary Mechanisms For Rad53 Dmentioning

confidence: 99%

Termination of Replication Stress Signaling via Concerted Action of the Slx4 Scaffold and the PP4 Phosphatase

et al. 2015

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In response to replication stress, signaling mediated by DNA damage checkpoint kinases protects genome integrity. However, following repair or bypass of DNA lesions, checkpoint signaling needs to be terminated for continued cell cycle progression and proliferation. In budding yeast, the PP4 phosphatase has been shown to play a key role in preventing hyperactivation of the checkpoint kinase Rad53. In addition, we recently uncovered a phosphatase-independent mechanism for downregulating Rad53 in which the DNA repair scaffold Slx4 decreases engagement of the checkpoint adaptor Rad9 at DNA lesions. Here we reveal that proper termination of checkpoint signaling following the bypass of replication blocks imposed by alkylated DNA adducts requires the concerted action of these two fundamentally distinct mechanisms of checkpoint downregulation. Cells lacking both SLX4 and the PP4-subunit PPH3 display a synergistic increase in Rad53 signaling and are exquisitely sensitive to the DNA alkylating agent methyl methanesulfonate, which induces replication blocks and extensive formation of chromosomal linkages due to template switching mechanisms required for fork bypass. Rad53 hypersignaling in these cells seems to converge to a strong repression of Mus81-Mms4, the endonuclease complex responsible for resolving chromosomal linkages, thus explaining the selective sensitivity of slx4D pph3D cells to alkylation damage. Our results support a model in which Slx4 acts locally to downregulate Rad53 activation following fork bypass, while PP4 acts on pools of active Rad53 that have diffused from the site of lesions. We propose that the proper spatial coordination of the Slx4 scaffold and PP4 action is crucial to allow timely activation of Mus81-Mms4 and, therefore, proper chromosome segregation.

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“…In addition to STR-dependent dissolution, which is the main pathway used by cells, HJs can also be processed through nucleolytic resolution using resolvases (Sarbajna and West 2014); however, this pathway can lead to crossover or noncrossover products, depending on the orientation of the cleavage at the junction. Indeed, cells lacking Sgs1 show an elevated frequency of sister chromatid exchanges (SCEs), which is reduced by inactivation of HJ resolvases like Mus81 or Slx4 (Wechsler et al 2011).…”

mentioning

confidence: 99%

Sgs1's roles in DNA end resection, HJ dissolution, and crossover suppression require a two-step SUMO regulation dependent on Smc5/6

et al. 2016

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The RecQ helicase Sgs1 plays critical roles during DNA repair by homologous recombination, from end resection to Holliday junction (HJ) dissolution. Sgs1 has both pro-and anti-recombinogenic roles, and therefore its activity must be tightly regulated. However, the controls involved in recruitment and activation of Sgs1 at damaged sites are unknown. Here we show a two-step role for Smc5/6 in recruiting and activating Sgs1 through SUMOylation. First, auto-SUMOylation of Smc5/6 subunits leads to recruitment of Sgs1 as part of the STR (Sgs1-Top3-Rmi1) complex, mediated by two SUMO-interacting motifs (SIMs) on Sgs1 that specifically recognize SUMOylated Smc5/6. Second, Smc5/6-dependent SUMOylation of Sgs1 and Top3 is required for the efficient function of STR. Sgs1 mutants impaired in recognition of SUMOylated Smc5/6 (sgs1-SIMΔ) or SUMO-dead alleles (sgs1-KR) exhibit unprocessed HJs at damaged replication forks, increased crossover frequencies during double-strand break repair, and severe impairment in DNA end resection. Smc5/6 is a key regulator of Sgs1's recombination functions.

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Holliday junction processing enzymes as guardians of genome stability

Cited by 92 publications

References 86 publications

Defects in homologous recombination repair behind the human diseases: FA and HBOC

Defects in homologous recombination repair behind the human diseases: FA and HBOC

Termination of Replication Stress Signaling via Concerted Action of the Slx4 Scaffold and the PP4 Phosphatase

Sgs1's roles in DNA end resection, HJ dissolution, and crossover suppression require a two-step SUMO regulation dependent on Smc5/6

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