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

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.

journal_name

Mol Cell

journal_title

Molecular cell

authors

Shibata A,Moiani D,Arvai AS,Perry J,Harding SM,Genois MM,Maity R,van Rossum-Fikkert S,Kertokalio A,Romoli F,Ismail A,Ismalaj E,Petricci E,Neale MJ,Bristow RG,Masson JY,Wyman C,Jeggo PA,Tainer JA

doi

10.1016/j.molcel.2013.11.003

subject

Has Abstract

pub_date

2014-01-09 00:00:00

pages

7-18

issue

1

eissn

1097-2765

issn

1097-4164

pii

S1097-2765(13)00828-9

journal_volume

53

pub_type

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