DNA double-strand break repair pathway choice is directed by distinct MRE11 nuclease activities.

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Abstract

MRE11 within the MRE11-RAD50-NBS1 (MRN) complex acts in DNA double-strand break repair (DSBR), detection, and signaling; yet, how its endo- and exonuclease activities regulate DSBR by nonhomologous end-joining (NHEJ) versus homologous recombination (HR) remains enigmatic. Here, we employed structure-based design with a focused chemical library to discover specific MRE11 endo- or exonuclease inhibitors. With these inhibitors, we examined repair pathway choice at DSBs generated in G2 following radiation exposure. While nuclease inhibition impairs radiation-induced replication protein A (RPA) chromatin binding, suggesting diminished resection, the inhibitors surprisingly direct different repair outcomes. Endonuclease inhibition promotes NHEJ in lieu of HR, while exonuclease inhibition confers a repair defect. Collectively, the results describe nuclease-specific MRE11 inhibitors, define distinct nuclease roles in DSB repair, and support a mechanism whereby MRE11 endonuclease initiates resection, thereby licensing HR followed by MRE11 exonuclease and EXO1/BLM bidirectional resection toward and away from the DNA end, which commits to HR.

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Journal

Journal ID (iso-abbrev): Mol Cell

Title: Molecular cell

Publisher: Elsevier BV

ISSN (Electronic): 1097-4164

ISSN (Print): 1097-2765

Publication date (Electronic): Jan 09 2014

Volume: 53

Issue: 1

Affiliations

[1 ] Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK; Advanced Scientific Research Leaders Development Unit, Gunma University, Maebashi, Gunma 371-8511, Japan.

[2 ] Skaggs Institute of Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; The Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.

[3 ] Skaggs Institute of Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; The Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; The School of Biotechnology, Amrita University, Kollam, Kerala 690525, India.

[4 ] Departments of Radiation Oncology and Medical Biophysics, University of Toronto, ON M5G 2M9, Canada.

[5 ] Genome Stability Laboratory, Laval University Cancer Research Center, Hôtel-Dieu de Québec, 9 McMahon, QC G1R 2J6, Canada.

[6 ] Department of Radiation Oncology, Department of Genetics, Erasmus University Medical Center, P.O. Box 2040, Rotterdam 3000 CA, the Netherlands.

[7 ] Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Via A. Moro, 53100 Siena, Italy.

[8 ] Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK.

[9 ] Genome Damage and Stability Centre, University of Sussex, Brighton BN1 9RQ, UK. Electronic address: p.a.jeggo@sussex.ac.uk.

[10 ] Skaggs Institute of Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; The Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. Electronic address: jatainer@lbl.gov.

Article

Publisher Item ID: S1097-2765(13)00828-9 Mid ID: NIHMS546540

DOI: 10.1016/j.molcel.2013.11.003

PMC ID: 3909494

PubMed ID: 24316220

SO-VID: d21474fd-3890-40b3-907a-9f167e9ebdce

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