MAD2L2 Promotes NHEJ at DSBs and Telomeres via 5′ End Resection Inhibition

Proper regulation of error-free homologous recombination (HR)–mediated repair at DNA double-strand breaks (DSB) and telomeres is required for genomic stability and is orchestrated by a complex network of proteins including BRCA1. Defects in HR activity fuel the acquisition of genomic alterations and confer dependency on parallel DNA repair pathways that have been targeted using PARP1 inhibitors. To identify regulators of telomere-induced genomic instability and nonhomologous end-joining (NHEJ)–dependent repair of uncapped telomeres, Boersma, Moatti, and colleagues performed a functional genetic screen. Suppression of mitotic arrest deficient-like 2 (MAD2L2, also known as REV7) prevented telomere fusion and enhanced cell survival. Mechanistically, MAD2L2 was recruited to exposed telomeres and sites of irradiation-induced DSBs and promoted NHEJ activity in multiple contexts by inhibiting CtBP-interacting protein (CTIP)–dependent and exonuclease 1–dependent 5′ DNA end resection independent of PAX-interacting protein 1 and the other components of DNA polymerase ζ (Polζ), REV1 and REV3. In a parallel study, Xu, Chapman, Brandsma, and colleagues identified MAD2L2 suppression as a mediator of resistance to the PARP1 inhibitor olaparib in BRCA1-deficient tumor cells both in vitro and in vivo. MAD2L2 depletion promoted olaparib resistance by increasing CTIP-dependent DNA end resection, restoring HR activity in BRCA1-deficient cells independent of the Polζ-associated function in translesion synthesis. Importantly, both groups found that MAD2L2 recruitment to DSBs was dependent on ATM kinase activity, histone H2AX, mediator of DNA damage checkpoint 1, ring finger protein 8 (RNF8), RNF168, and p53-binding protein 1 (53BP1), with Boersma, Moatti, and colleagues also showing dependence on RAP-interacting factor 1 (RIF1). In addition, both groups found that MAD2L2 loss inhibited NHEJ activity and decreased class switch recombination, similar to the effects of 53BP1 ablation. Together, these data highlight a critical role for MAD2L2 in the regulation of DNA repair pathway decisions downstream of 53BP1 and suggest that MAD2L2 loss may compromise genomic integrity.

Boersma V, Moatti N, Segura-Bayona S, Peuscher MH, van der Torre J, Wevers BA, et al. MAD2L2 controls DNA repair at telomeres and DNA breaks by inhibiting 5′ end resection. Nature 2015 Mar 23 [Epub ahead of print].

Xu G, Chapman JR, Brandsma I, Yuan J, Mistrik M, Bouwman P, et al. REV7 counteracts DNA double-strand break resection and affects PARP inhibition. Nature 2015 Mar 23 [Epub ahead of print].

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