Fission Yeast Exo1 and Rqh1-Dna2 Redundantly Contribute to Resection of Uncapped Telomeres

Nanbu, Tomoko; Nguyen, Luan Cao; Habib, Ahmed G. K.; Hirata, Naoya; Ukimori, Shinobu; Tanaka, Daiki; Masuda, Kenta; Takahashi, Katsunori; Yukawa, Masashi; Tsuchiya, Eiko; Ueno, Masaru

doi:10.1371/journal.pone.0140456

Cited by 12 publications

(9 citation statements)

References 42 publications

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“…A moderate role for Rqh1 in end resection is also reported in a previous study (32). But Rqh1 has been shown to have an important role in end resection and homologous recombination in other studies (37,38). The biochemical properties of Dna2 have been thoroughly characterized in vitro; it preferentially cleaves a flap DNA structure (39).…”

Section: Cdc24 Functions In Long-range End Resectionsupporting

confidence: 53%

Cdc24 Is Essential for Long-range End Resection in the Repair of Double-stranded DNA Breaks

Zhang¹,

Yu²,

Li³

et al. 2016

Journal of Biological Chemistry

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Edited by Patrick SungDouble-stranded DNA breaks (DSBs) are highly detrimental DNA lesions, which may be repaired by the homologous recombination-mediated repair pathway. The 5 to 3 direction of long-range end resection on one DNA strand, in which 3-single-stranded DNA overhangs are created from broken DNA ends, is an essential step in this pathway. Dna2 has been demonstrated as an essential nuclease in this event, but the molecular mechanism of how Dna2 is recruited to DNA break sites in vivo has not been elucidated. In this study, a novel recombination factor called Cdc24 was identified in fission yeast. We demonstrated that Cdc24 localizes to DNA break sites during the repair of DNA breaks and is an essential factor in long-range end resection. We also determined that Cdc24 plays a direct role in recruiting Dna2 to DNA break sites through its interaction with Dna2 and replication protein A (RPA). Further, this study revealed that RPA acts as the foundation for assembling the machinery for long-range end resection by its essential role in recruiting Cdc24 and Dna2 to DNA break sites. These results define Cdc24 as an essential factor for long-range end resection in the repair of DSBs, opening the door for further investigations into the enzymes involved in long-range end resection for DSB repair. Double-stranded DNA breaks (DSBs) 2 are one of the most cytotoxic DNA lesions. DSBs can occur naturally inside cells (e.g. meiotic recombination, mating type switch, or V(D)J exchange); they can also be caused by endogenous reactive metabolites and extracellular agents (e.g. UV, IR, and chemical agents such as camptothecin (CPT)) (1). If DSBs are left unrepaired or are repaired inappropriately, it will lead to a variety of mutations such as deletions, insertions, translocation, and genetic fusions, resulting in drastic genomic instability (2, 3).Eukaryotic cells have two major and conserved pathways to repair DSBs: non-homologous end joining (NHEJ) and homologous recombination (HR) (4). In NHEJ, two broken DNA ends are rejoined by the concerted actions of Ku70/80, DNAPKcs, DNA ligase IV, and some other proteins and enzymes (5). NHEJ does not need a homologous DNA sequence for the repair of DSBs, so it can occur in any phase of the cell cycles but dominates at G 0 /G 1 (6). Compared with HR, NHEJ is an errorprone pathway because genetic deletion or insertion of a few base pairs is frequently observed at the break-rejoining site (7,8). HR requires a homologous DNA template that is present in a sister chromatid or an ectopic DNA sequence to fix breaks. Therefore, the HR pathway dominates at the S and G 2 phases and is a relatively error-free repair pathway, although genetic mutations can occur at times (9, 10). A central step in the HR pathway is the 5Ј to 3Ј digestion on one DNA strand from broken DNA ends to generate 3Ј-ended single-stranded DNA (ssDNA) overhangs, a process termed DNA end resection (11,12). The HR-mediated repair of DSBs is reliant on this end resection because only ssDNA is able to invade a homologou...

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Section: Cdc24 Functions In Long-range End Resectionsupporting

confidence: 53%

Cdc24 Is Essential for Long-range End Resection in the Repair of Double-stranded DNA Breaks

Zhang¹,

Yu²,

Li³

et al. 2016

Journal of Biological Chemistry

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“…Essential to the mechanism of telomere capping is the generation of a 3′ overhang at telomere ends to form the t-loop. In mammals and yeast, two nucleases, EXO1 and DNA2, contribute to the generation of the G-overhang (20,42). To determine the contribution, if any, of CtIP to this overhang, G-overhang lengths were assayed by a conventional non-denaturing in-gel hybridization analysis.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, DNA2 and EXO1 depend on the activity and presence of CtIP to perform proper resection at DNA breaks (17,18). These activities of CtIP may extend from DSBs to telomeres as EXO1 and DNA2 have also been implicated in the generation of the G-overhang at telomeric ends (19,20). Similarly, MRN functions at dysfunctional telomeres to promote 3′-overhang generation and suppress NHEJ at telomeric ends (21).…”

Section: Introductionmentioning

confidence: 99%

CtIP is essential for telomere replication

Stroik

Kurtz

Hendrickson

2019

Nucleic Acids Research

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The maintenance of telomere length is critical to longevity and survival. Specifically, the failure to properly replicate, resect, and/or form appropriate telomeric structures drives telomere shortening and, in turn, genomic instability. The endonuclease CtIP is a DNA repair protein that is well-known to promote genome stability through the resection of endogenous DNA double-stranded breaks. Here, we describe a novel role for CtIP. We show that in the absence of CtIP, human telomeres shorten rapidly to non-viable lengths. This telomere dysfunction results in an accumulation of fusions, breaks, and frank telomere loss. Additionally, CtIP suppresses the generation of circular, extrachromosomal telomeric DNA. These latter structures appear to arise from arrested DNA replication forks that accumulate in the absence of CtIP. Hence, CtIP is required for faithful replication through telomeres via its roles at stalled replication tracts. Our findings demonstrate a new role for CtIP as a protector of human telomere integrity.

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“…Pxd1 was identified as a regulator of DSB repair by the single-strand annealing (SSA) pathway; it physically interacts not only with Dna2, but also with Rad16, thereby regulating the activity of the two nucleases and improving SSA outcomes [163]. On the other hand, Exo1 and Rqh1-Dna2 play redundant roles in resection of uncapped telomeres arising from deletion of pot1 [164].…”

Section: Roles Of Sgs1 In Dsb Repairmentioning

confidence: 99%

Maintenance of Yeast Genome Integrity by RecQ Family DNA Helicases

Gupta

Schmidt

2020

Genes

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With roles in DNA repair, recombination, replication and transcription, members of the RecQ DNA helicase family maintain genome integrity from bacteria to mammals. Mutations in human RecQ helicases BLM, WRN and RecQL4 cause incurable disorders characterized by genome instability, increased cancer predisposition and premature adult-onset aging. Yeast cells lacking the RecQ helicase Sgs1 share many of the cellular defects of human cells lacking BLM, including hypersensitivity to DNA damaging agents and replication stress, shortened lifespan, genome instability and mitotic hyper-recombination, making them invaluable model systems for elucidating eukaryotic RecQ helicase function. Yeast and human RecQ helicases have common DNA substrates and domain structures and share similar physical interaction partners. Here, we review the major cellular functions of the yeast RecQ helicases Sgs1 of Saccharomyces cerevisiae and Rqh1 of Schizosaccharomyces pombe and provide an outlook on some of the outstanding questions in the field.

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Fission Yeast Exo1 and Rqh1-Dna2 Redundantly Contribute to Resection of Uncapped Telomeres

Cited by 12 publications

References 42 publications

Cdc24 Is Essential for Long-range End Resection in the Repair of Double-stranded DNA Breaks

Cdc24 Is Essential for Long-range End Resection in the Repair of Double-stranded DNA Breaks

CtIP is essential for telomere replication

Maintenance of Yeast Genome Integrity by RecQ Family DNA Helicases

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