REV7/MAD2L2: the multitasking maestro emerges as a barrier to recombination

Abstract

REV7/MAD2L2 plays important roles in translesion DNA synthesis and mitotic control. Two new papers extend its gamut by revealing its unexpected participation in pathway choice during DNA double-strand break repair. By inhibiting 5′ DNA end resection downstream of 53BP1 and RIF1, REV7/MAD2L2 promotes non-homologous end joining at the expense of homologous recombination. Importantly, loss of REV7/MAD2L2 renders PARP inhibitors ineffective in BRCA1-deficient tumours, suggesting another possible mechanism for the acquisition of resistance to this important new class of drug.

Figure 1. The cellular roles of MAD2L2

(A) MAD2L2 helps coordinate nucleotide insertion opposite a lesion by Y-family polymerases with mismatch extension by REV3/Polζ during translesion synthesis. (B) MAD2L2 helps to prevent premature activation of the APC/C by sequestering CDH1. (C) The newly uncovered role for MAD2L2 in pathway choice during double-strand break repair. A highly stripped-down scheme of the DNA damage response showing the role of 53BP1 in limiting resection through recruitment of RIF1. Genetically, MAD2L2 appears to act downstream of RIF1. BRCA1 and phosphorylated CtIP prevent RIF1 recruitment, allowing displacement of 53BP1, resection and recombination. Thus, in the absence of BRCA1, 53BP1 and MAD2L2 block resection. Removing either of these factors in BRCA1-deficient cells alleviates this block and can allow resection to proceed.