Saccharomyces cerevisiae Mre11/Rad50/Xrs2 and Ku proteins regulate association of Exo1 and Dna2 with DNA breaks

Shim, Eun Yong; Chung, Woo Hyun; Nicolette, Matthew L.; Zhang, Yu; Davis, Melody; Zhu, Zhu; Paull, Tanya T.; Ira, Grzegorz; Lee, Sang Eun

doi:10.1038/emboj.2010.219

Cited by 212 publications

(301 citation statements)

References 53 publications

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“…Mre11, one of the first proteins bound to DSB sites, provides a structural platform for the initial recruitment of Dna2 to DSB sites (49,50). It was noted that the level of Dna2 associated near the DSB sites increased during resection (50). This observation cannot be explained only by the proteinprotein interactions between Dna2 and Mre11 (or Sgs1 at the later stage).…”

Section: Discussionmentioning

confidence: 67%

“…Dna2 cleaves selectively the 5Ј-overhang ssDNA of the Y-structured DNA, producing a 3Ј-ss overhang (8). Mre11, one of the first proteins bound to DSB sites, provides a structural platform for the initial recruitment of Dna2 to DSB sites (49,50). It was noted that the level of Dna2 associated near the DSB sites increased during resection (50).…”

Section: Discussionmentioning

confidence: 99%

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The N-terminal 45-kDa Domain of Dna2 Endonuclease/Helicase Targets the Enzyme to Secondary Structure DNA

Lee

Kang

et al. 2013

Journal of Biological Chemistry

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Background:The biochemical function of variable N-terminal regions of eukaryotic Dna2 remains unclear. Results: The N-terminal 45-kDa domain of yeast Dna2 targets the enzyme specifically to a secondary structure flap. Conclusion:The hairpin binding activity of Dna2 contributes to efficient removal of hairpin flaps together with endonuclease and helicase activities during Okazaki fragment processing. Significance: The hairpin binding activity of Dna2 is critical for genome stability.

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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

The N-terminal 45-kDa Domain of Dna2 Endonuclease/Helicase Targets the Enzyme to Secondary Structure DNA

Lee

Kang

et al. 2013

Journal of Biological Chemistry

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“…In yeast, the need of MRX for end resection can be bypassed in the absence of Ku (26,27). Interestingly, we found that elevated MMEJ due to Ku70 deficiency was greatly reduced by loss of Mre11 or Mre11 nuclease activity ( Fig.…”

Section: Mre11mentioning

confidence: 67%

“…We showed that the nuclease activity of human Mre11 is required for initial end resection and cannot be substituted by other nucleases such as BLM and Exo1. Third, loss of Ku70 in yeast can bypass the requirement of MRN for end resection (26,27), whereas, in mammalian cells, elevated MMEJ and HR in Ku70-or Ku80-deficient cells are still dependent on the Mre11 complex and Mre11 nuclease activity, even with DSB ends generated by the I-SceI endonuclease in our study. This finding is supported by the in vitro analysis using Xenopus extracts where depletion of Mre11 blocks end resection from restriction enzyme-generated DSBs from the very initial step at the first nucleotide (45).…”

Section: Mmej Is Used To Repair Dsbs Occurring At Collapsed Replicationmentioning

confidence: 74%

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Microhomology-mediated End Joining and Homologous Recombination share the initial end resection step to repair DNA double-strand breaks in mammalian cells

Truong

Shi

et al. 2013

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

425

453

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Microhomology-mediated end joining (MMEJ) is a major pathway for Ku-independent alternative nonhomologous end joining, which contributes to chromosomal translocations and telomere fusions, but the underlying mechanism of MMEJ in mammalian cells is not well understood. In this study, we demonstrated that, distinct from Ku-dependent classical nonhomologous end joining, MMEJ-even with very limited end resection-requires cyclin-dependent kinase activities and increases significantly when cells enter S phase. We also showed that MMEJ shares the initial end resection step with homologous recombination (HR) by requiring meiotic recombination 11 homolog A (Mre11) nuclease activity, which is needed for subsequent recruitment of Bloom syndrome protein (BLM) and exonuclease 1 (Exo1) to DNA double-strand breaks (DSBs) to promote extended end resection and HR. MMEJ does not require S139-phosphorylated histone H2AX (γ-H2AX), suggesting that initial end resection likely occurs at DSB ends. Using a MMEJ and HR competition repair substrate, we demonstrated that MMEJ with short end resection is used in mammalian cells at the level of 10-20% of HR when both HR and nonhomologous end joining are available. Furthermore, MMEJ is used to repair DSBs generated at collapsed replication forks. These studies suggest that MMEJ not only is a backup repair pathway in mammalian cells, but also has important physiological roles in repairing DSBs to maintain cell viability, especially under genomic stress.BLM/Exo1 | CtIP | DNA repair pathway | DNA damage | genome stability D NA double-strand breaks (DSBs) can be repaired by multiple pathways. The classical nonhomologous end joining (C-NHEJ) pathway relies on Ku70/Ku80 and ligates DSB ends without a template (1). Homologous recombination (HR), an error-free pathway, uses a homologous template to repair DSBs (2) and is initiated by end resection from DSB ends to generate a long stretch of singlestrand DNA (ssDNA) for strand invasion. Although C-NHEJ is active throughout the cell cycle, HR is used when cells enter S and G2 because cyclin-dependent kinases (CDKs) are needed for promoting end resection to activate HR (3-5).In the absence of C-NHEJ factors such as Ku70, Ku80, or DNA ligase IV, robust alternative nonhomologous end joining (alt-NHEJ) activity is observed in various organisms including yeast and mammals (6, 7). Many alt-NHEJ events, classified as microhomology-mediated end joining (MMEJ), require end resection and join the ends by base pairing at microhomology sequences (5-25 nucleotides), resulting in deletions at the junctions (6). However, other alt-NHEJ pathways without using microhomology regions also exist.Genetic analyses in yeast reveal that MMEJ is Rad52-independent, distinguishing it from HR and single-strand annealing (SSA) repair pathways, whereas the Mre11-Rad50-Xrs2 (MRX) complex and DNA ligase IV are needed for MMEJ (8-10). Further studies suggest that in yeast, Srs2 helicase, Sae2 nuclease [CtBP-interacting protein (CtIP) homologue], Tel1 [ataxia telangiectasia mutated (A...

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Saccharomyces cerevisiae Rif1 cooperates with MRX-Sae2 in promoting DNA-end resection

et al. 2014

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Diverse roles in DNA metabolism have been envisaged for budding yeast and mammalian Rif1. In particular, yeast Rif1 is involved in telomere homeostasis, while its mammalian counterpart participates in the cellular response to DNA double-strand breaks (DSBs). Here, we show that Saccharomyces cerevisiae Rif1 supports cell survival to DNA lesions in the absence of MRX or Sae2. Furthermore, it contributes to the nucleolytic processing (resection) of DSBs. This Rif1-dependent control of DSB resection becomes important for DSB repair by homologous recombination when resection activities are suboptimal.

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Saccharomyces cerevisiae Mre11/Rad50/Xrs2 and Ku proteins regulate association of Exo1 and Dna2 with DNA breaks

Cited by 212 publications

References 53 publications

The N-terminal 45-kDa Domain of Dna2 Endonuclease/Helicase Targets the Enzyme to Secondary Structure DNA

The N-terminal 45-kDa Domain of Dna2 Endonuclease/Helicase Targets the Enzyme to Secondary Structure DNA

Microhomology-mediated End Joining and Homologous Recombination share the initial end resection step to repair DNA double-strand breaks in mammalian cells

Saccharomyces cerevisiae Rif1 cooperates with MRX-Sae2 in promoting DNA-end resection

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