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

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

  • Mol Cell. 2014 Jan 9;53(1):7-18. doi: 10.1016/j.molcel.2013.11.003.
Atsushi Shibata 1,  Davide Moiani 2,  Andrew S Arvai 2,  Jefferson Perry 3,  Shane M Harding 4,  Marie-Michelle Genois 5,  Ranjan Maity 5,  Sari van Rossum-Fikkert 6,  Aryandi Kertokalio 6,  Filippo Romoli 7,  Amani Ismail 8,  Ermal Ismalaj 7,  Elena Petricci 7,  Matthew J Neale 8,  Robert G Bristow 4,  Jean-Yves Masson 5,  Claire Wyman 6,  Penny A Jeggo 9,  John A Tainer 10
Affiliations

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.
PMID: 24316220 DOI: 10.1016/j.molcel.2013.11.003
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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