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

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posted on 2023-06-08, 16:51 authored by Atsushi Shibata, Davide Moiani, Andrew S Arvai, Jefferson Perry, Shane M Harding, Marie-Michelle Genois, Ranjan Maity, Sari van Rossum-Fikkert, Aryandi Kertokalio, Filipo Romoli, Amani Ismail, Ermal Ismalaj, Elena Petricci, Matt NealeMatt Neale, Robert G Bristow, Jean-Yves Masson, Claire Wyman, Penny Jeggo, John A Tainer
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.

History

Publication status

  • Published

File Version

  • Accepted version

Journal

Molecular Cell

ISSN

1097-2765

Publisher

Elsevier

Issue

1

Volume

53

Page range

7-18

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2014-03-12

First Open Access (FOA) Date

2014-03-12

First Compliant Deposit (FCD) Date

2014-03-12

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