TY - JOUR
T1 - DNA Double-Strand Break Repair Pathway Choice Is Directed by Distinct MRE11 Nuclease Activities
AU - Shibata, Atsushi
AU - Moiani, Davide
AU - Arvai, Andrew S.
AU - Perry, Jefferson
AU - Harding, Shane M.
AU - Genois, Marie Michelle
AU - Maity, Ranjan
AU - van Rossum-Fikkert, Sari
AU - Kertokalio, Aryandi
AU - Romoli, Filippo
AU - Ismail, Amani
AU - Ismalaj, Ermal
AU - Petricci, Elena
AU - Neale, Matthew J.
AU - Bristow, Robert G.
AU - Masson, Jean Yves
AU - Wyman, Claire
AU - Jeggo, Penny A.
AU - Tainer, John A.
PY - 2014/1/9
Y1 - 2014/1/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84892369333&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2013.11.003
DO - 10.1016/j.molcel.2013.11.003
M3 - Article
C2 - 24316220
AN - SCOPUS:84892369333
SN - 1097-2765
VL - 53
SP - 7
EP - 18
JO - Molecular Cell
JF - Molecular Cell
IS - 1
ER -
