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

Shibata, Atsushi, Moiani, Davide, Arvai, Andrew S, Perry, Jefferson, Harding, Shane M, Genois, Marie-Michelle, Maity, Ranjan, van Rossum-Fikkert, Sari, Kertokalio, Aryandi, Romoli, Filipo, Ismail, Amani, Ismalaj, Ermal, Petricci, Elena, Neale, Matthew J, Bristow, Robert G, Masson, Jean-Yves, Wyman, Claire, Jeggo, Penny and Tainer, John A (2014) DNA double-strand break repair pathway shoice is directed by distinct MRE11 nuclease activities. Molecular Cell, 53 (1). pp. 7-18. ISSN 1097-2765

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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.

Item Type: Article
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Subjects: Q Science
Depositing User: Gee Wheatley
Date Deposited: 12 Mar 2014 07:22
Last Modified: 06 Mar 2017 21:09
URI: http://sro.sussex.ac.uk/id/eprint/47814

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