Figure 9.

Model for ZMYM2 functions in promoting HR repair of DSBs. The ZnF proteins ZMYM2 and ZMYM3 localize to damaged DNA lesions where they function to antagonize 53BP1. ZMYM2 is an effector of SUMOylation at break sites, where it localizes to DSBs in a PIAS4-dependent manner that also involves its ZnF domains. Once localized to damage sites, the SIM2 and SIM3 domains of ZMYM2 are required to inhibit break-associated 53BP1 in a SUMO-binding dependent mechanism. In cells lacking this pathway, including ZMYM2-deficient cells, 53BP1 is hyper-loaded onto break sites where it out competes BRCA1, resulting in defective HR repair. This work identifies a new pathway critical for balancing the chromatin association of BRCA1 and 53BP1 to promote efficient DSB repair in human cells.