Sgs1 and Sae2 promote telomere replication by limiting accumulation of ssDNA

Hardy, Julien; Churikov, Dmitri; Géli, Vincent; Simon, Marie‐Noëlle

doi:10.1038/ncomms6004

Cited by 36 publications

(38 citation statements)

References 70 publications

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“…Wild-type and mre11-P110L cells progressed to G 2 /M 1 h after removal of MMS from the culture, initiated division at 2 h, and by 4 h, the FACS profile was similar to untreated cells. By contrast, sae2Δ cells remained in S phase for 2 h after removal of MMS from the culture and had not resumed division at 4 h, consistent with impaired DNA replication (30). The mre11-P110L mutation partially suppressed the S-phase progression defect caused by sae2Δ, and cells resumed division 3 h after MMS treatment.…”

Section: Mre11-p110l Bypasses the Checkpoint And Cell Cycle Progressionmentioning

confidence: 88%

Sae2 promotes DNA damage resistance by removing the Mre11–Rad50–Xrs2 complex from DNA and attenuating Rad53 signaling

Chen

Donnianni

Handa

et al. 2015

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

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The Mre11-Rad50-Xrs2/NBS1 (MRX/N) nuclease/ATPase complex plays structural and catalytic roles in the repair of DNA doublestrand breaks (DSBs) and is the DNA damage sensor for Tel1/ATM kinase activation. Saccharomyces cerevisiae Sae2 can function with MRX to initiate 5′-3′ end resection and also plays an important role in attenuation of DNA damage signaling. Here we describe a class of mre11 alleles that suppresses the DNA damage sensitivity of sae2Δ cells by accelerating turnover of Mre11 at DNA ends, shutting off the DNA damage checkpoint and allowing cell cycle progression. The mre11 alleles do not suppress the end resection or hairpinopening defects of the sae2Δ mutant, indicating that these functions of Sae2 are not responsible for DNA damage resistance. The purified M P110L RX complex shows reduced binding to single-and double-stranded DNA in vitro relative to wild-type MRX, consistent with the increased turnover of Mre11 from damaged sites in vivo. Furthermore, overproduction of Mre11 causes DNA damage sensitivity only in the absence of Sae2. Together, these data suggest that it is the failure to remove Mre11 from DNA ends and attenuate Rad53 kinase signaling that causes hypersensitivity of sae2Δ cells to clastogens.DNA repair | Mre11 | Sae2 | DNA damage checkpoint

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Section: Mre11-p110l Bypasses the Checkpoint And Cell Cycle Progressionmentioning

confidence: 88%

Sae2 promotes DNA damage resistance by removing the Mre11–Rad50–Xrs2 complex from DNA and attenuating Rad53 signaling

Chen

Donnianni

Handa

et al. 2015

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

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“…Mutation of MRE11 or RAD50 does not cause lethality in the sgs1Δ background, although cells grow very slowly, suggesting the sae2Δ sgs1Δ lethality is not due solely to the end resection defect (Bernstein et al, 2013). Moreover, the mre11Δ sae2Δ sgs1Δ triple mutant is viable suggesting it is retention of MRX at ends that causes lethality in sae2Δ sgs1Δ cells (Hardy et al, 2014). The mre11-nd sgs1Δ double mutant is viable, but grows slowly and early resection is greatly reduced (Mimitou and Symington, 2010; Shim et al, 2010; Budd and Campbell, 2009).…”

Section: Extensive Resection By Exo1 and Dna2mentioning

confidence: 99%

Mechanism and regulation of DNA end resection in eukaryotes

Symington

2016

Critical Reviews in Biochemistry and Molecular Biology

355

402

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The repair of DNA double-strand breaks (DSBs) by homologous recombination (HR) is initiated by nucleolytic degradation of the 5′ terminated strands in a process termed end resection. End resection generates 3′ single-stranded DNA tails, substrates for Rad51 to catalyze homologous pairing and exchange of DNA strands, and for activation of the DNA damage checkpoint. The commonly accepted view is that end resection occurs by a two-step mechanism. In the first step, Sae2/CtIP activates the Mre11-Rad50-Xrs2/Nbs1 (MRX/N) complex to endonucleolytically cleave the 5′-terminated DNA strands close to break ends, and in the second step Exo1 and/or Dna2 nucleases extend the resected tracts to produce long 3′-ssDNA-tailed intermediates. Initiation of resection commits a cell to repair a DSB by HR because long ssDNA overhangs are poor substrates for non-homologous end joining (NHEJ). Thus, the initiation of end resection has emerged as a critical control point for repair pathway choice. Here, I review recent studies on the mechanism of end resection and how this process is regulated to ensure the most appropriate repair outcome.

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“…Heterozygous EST2/est2Δ diploids harboring the pGAL::Yra1Δi plasmid were sporulated in glucose medium. Next, haploid est2Δ pGAL::Yra1Δi spore clones were selected in glucose medium and further propagated in galactose liquid medium via serial dilutions (Hardy et al 2014). The senescence profiles, kinetics of telomere shortening, and the type of survivors formed in multiple est2Δ and est2Δ pGAL::Yra1Δi clones grown in galactose were analyzed (Fig.…”

Section: Yra1-stabilized R Loops Induce Instability Regardless Of Tramentioning

confidence: 99%

“…Replicative senescence was calculated as the average of two to 10 independent spores with identical genotype. Telomere analysis of the samples was performed as described Hardy et al 2014).…”

Section: Senescence Assays and Telomere Analysismentioning

confidence: 99%

Yra1-bound RNA–DNA hybrids cause orientation-independent transcription–replication collisions and telomere instability

García-Rubio¹,

Aguilera²,

Lafuente-Barquero³

et al. 2018

Genes Dev.

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R loops are an important source of genome instability, largely due to their negative impact on replication progression. Yra1/ALY is an abundant RNA-binding factor conserved from yeast to humans and required for mRNA export, but its excess causes lethality and genome instability. Here, we show that, in addition to ssDNA and ssRNA, Yra1 binds RNA-DNA hybrids in vitro and, when artificially overexpressed, can be recruited to chromatin in an RNA-DNA hybrid-dependent manner, stabilizing R loops and converting them into replication obstacles in vivo. Importantly, an excess of Yra1 increases R-loop-mediated genome instability caused by transcription-replication collisions regardless of whether they are codirectional or head-on. It also induces telomere shortening in telomerasenegative cells and accelerates senescence, consistent with a defect in telomere replication. Our results indicate that RNA-DNA hybrids form transiently in cells regardless of replication and, after stabilization by excess Yra1, compromise genome integrity, in agreement with a two-step model of R-loop-mediated genome instability. This work opens new perspectives to understand transcription-associated genome instability in repair-deficient cells, including tumoral cells.

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Sgs1 and Sae2 promote telomere replication by limiting accumulation of ssDNA

Cited by 36 publications

References 70 publications

Sae2 promotes DNA damage resistance by removing the Mre11–Rad50–Xrs2 complex from DNA and attenuating Rad53 signaling

Sae2 promotes DNA damage resistance by removing the Mre11–Rad50–Xrs2 complex from DNA and attenuating Rad53 signaling

Mechanism and regulation of DNA end resection in eukaryotes

Yra1-bound RNA–DNA hybrids cause orientation-independent transcription–replication collisions and telomere instability

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