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

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
Mol Cell 53 7-18 (2014)
Related entries: 4o24, 4o43, 4o4k, 4o5g

Cited: 340 times
EuropePMC logo PMID: 24316220

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.

Reviews - 4nzv mentioned but not cited (1)

  1. Functional and structural insights into the MRX/MRN complex, a key player in recognition and repair of DNA double-strand breaks. Tisi R, Vertemara J, Zampella G, Longhese MP. Comput Struct Biotechnol J 18 1137-1152 (2020)

Articles - 4nzv mentioned but not cited (1)

  1. Targeting Allostery with Avatars to Design Inhibitors Assessed by Cell Activity: Dissecting MRE11 Endo- and Exonuclease Activities. Moiani D, Ronato DA, Brosey CA, Arvai AS, Syed A, Masson JY, Petricci E, Tainer JA. Methods Enzymol 601 205-241 (2018)


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