DNA Double-Strand Break Repair Pathway Choice Is Directed by Distinct MRE11 Nuclease Activities

Shibata, Atsushi; Moiani, Davide; Arvai, A.S.; Perry, J. Jefferson P.; Harding, Shane M.; Genois, Marie Michelle; Maity, Ranjan; Rossum-Fikkert, Sari van; Kertokalio, Aryandi; Romoli, F; Ismail, Amani; Ismalaj, Ermal; Petricci, Elena; Neale, Matthew J.; Bristow, Robert G.; Masson, Jean Yves; Wyman, Claire; Jeggo, Penny A.; Tainer, John A.

doi:10.1016/j.molcel.2014.01.008

Cited by 78 publications

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“…Sae2/CtIP cooperate with the Mre11/Rad50/Xrs2 (mammalian MRE11/ RAD50/NBS1) complex to provide the initial resection of DSBs. It is unclear whether Sae2/ CtIP phosphorylation affects the MRE11-associated exo-and endonuclease activities, which differentially affect pathway choice in DSB repair (Lengsfeld et al 2007;Cannavo and Cejka 2014;Shibata et al 2014). In addition, yeast Dna2, a nuclease/helicase that cooperates with Sgs1 and RPA in long-range resection, is recruited to DSBs in a CDK-phosphorylation-dependent manner .…”

Section: Dsb-repair Pathway Choice or How Resection Commits To Hrmentioning

confidence: 99%

Regulation of Recombination and Genomic Maintenance

Heyer

2015

Cold Spring Harb Perspect Biol

104

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Recombination is a central process to stably maintain and transmit a genome through somatic cell divisions and to new generations. Hence, recombination needs to be coordinated with other events occurring on the DNA template, such as DNA replication, transcription, and the specialized chromosomal functions at centromeres and telomeres. Moreover, regulation with respect to the cell-cycle stage is required as much as spatiotemporal coordination within the nuclear volume. These regulatory mechanisms impinge on the DNA substrate through modifications of the chromatin and directly on recombination proteins through a myriad of posttranslational modifications (PTMs) and additional mechanisms. Although recombination is primarily appreciated to maintain genomic stability, the process also contributes to gross chromosomal arrangements and copy-number changes. Hence, the recombination process itself requires quality control to ensure high fidelity and avoid genomic instability. Evidently, recombination and its regulatory processes have significant impact on human disease, specifically cancer and, possibly, neurodegenerative diseases.

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Section: Dsb-repair Pathway Choice or How Resection Commits To Hrmentioning

confidence: 99%

Regulation of Recombination and Genomic Maintenance

Heyer

2015

Cold Spring Harb Perspect Biol

104

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“…The MRN complex, and particularly MRE11, is reported to participate in the resection step of HR along with several DNA nucleases (CtIP [C-terminal binding protein interacting protein], EXO1 and DNA2). RAD51, another DNA repair protein, is then loaded in place of RPA on ssDNA regions; this exchange step is mediated by Rad52 in yeast or BRCA2 in vertebrates, and promotes the initiation of further HR steps (Mimitou and Symington, 2011;Thompson, 2012;Shibata et al, 2014). NBS1-or MRE11-deficient chicken DT40 or human cells showed remarkably decreased HR activity (Tauchi et al, 2002a;Sakamoto et al, 2007), suggesting the importance of the MRN complex in HR repair.…”

Section: Introductionmentioning

confidence: 99%

Chromatin modification and NBS1: their relationship in DNA double-strand break repair

2015

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The importance of chromatin modification, including histone modification and chromatin remodeling, for DNA double-strand break (DSB) repair, as well as transcription and replication, has been elucidated. Phosphorylation of H2AX to γ-H2AX is one of the first responses following DSB detection, and this histone modification is important for the DSB damage response by triggering several events, including the accumulation of DNA damage response-related proteins and subsequent homologous recombination (HR) repair. The roles of other histone modifications such as acetylation, methylation and ubiquitination have also been recently clarified, particularly in the context of HR repair. NBS1 is a multifunctional protein that is involved in various DNA damage responses. Its recently identified binding partner RNF20 is an E3 ubiquitin ligase that facilitates the monoubiquitination of histone H2B, a process that is crucial for recruitment of the chromatin remodeler SNF2h to DSB damage sites. Evidence suggests that SNF2h functions in HR repair, probably through regulation of end-resection. Moreover, several recent reports have indicated that SNF2h can function in HR repair pathways as a histone remodeler and that other known histone remodelers can also participate in DSB damage responses. On the other hand, information about the roles of such chromatin modifications and NBS1 in non-homologous end joining (NHEJ) repair of DSBs and stalled fork-related damage responses is very limited; therefore, these aspects and processes need to be further studied to advance our understanding of the mechanisms and molecular players involved.

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“…DNA substrates for endo-and exonuclease activity may bind distinctly in Mre11. Specific inhibitors for either endo-or exonuclease activity have been identified (46). Mutation of His-52 in Pfu-Mre11 eliminates exonuclease activity but only has a minor effect on endonuclease activity (43).…”

Section: Discussionmentioning

confidence: 99%

“…The endo-and exonuclease activities of Mre11 act at different stages during HR (46). Endonuclease activity initiates DSB resection and may affect pathway choice in DSB repair, whereas its exonuclease activity functions downstream.…”

Section: Discussionmentioning

confidence: 99%

Autoinhibition of Bacteriophage T4 Mre11 by Its C-terminal Domain

Gao

Nelson

2014

Journal of Biological Chemistry

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Background: How nuclease activity of Mre11 is controlled by Rad50 is poorly understood. Results: Removal of the C-terminal domain of T4 Mre11 enhances its nuclease activity. Conclusion: The C terminus of Mre11 is autoinhibitory, and complex formation with Rad50 relieves this inhibition. Significance: This autoinhibition provides a mechanism for restricting the nuclease activity of Mre11 in the absence of Rad50.

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DNA Double-Strand Break Repair Pathway Choice Is Directed by Distinct MRE11 Nuclease Activities

Cited by 78 publications

References 0 publications

Regulation of Recombination and Genomic Maintenance

Regulation of Recombination and Genomic Maintenance

Chromatin modification and NBS1: their relationship in DNA double-strand break repair

Autoinhibition of Bacteriophage T4 Mre11 by Its C-terminal Domain

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