H3K4 methylation by SETD1A/BOD1L facilitates RIF1-dependent NHEJ

The 53BP1-RIF1-shieldin pathway maintains genome stability by suppressing nucleolytic degradation of DNA ends at double-strand breaks (DSBs). Although RIF1 interacts with damaged chromatin via phospho-53BP1 and facilitates recruitment of the shieldin complex to DSBs, it is unclear whether other regulatory cues contribute to this response. Here, we implicate methylation of histone H3 at lysine 4 by SETD1A-BOD1L in the recruitment of RIF1 to DSBs. Compromising SETD1A or BOD1L expression or deregulating H3K4 methylation allows uncontrolled resection of DNA ends, impairs end-joining of dysfunctional telomeres, and abrogates class switch recombination. Moreover, defects in RIF1 localization to DSBs are evident in patient cells bearing loss-of-function mutations in SETD1A. Loss of SETD1A-dependent RIF1 recruitment in BRCA1-deficient cells restores homologous recombination and leads to resistance to poly(ADP-ribose)polymerase inhibition, reinforcing the clinical relevance of these observations. Mechanistically, RIF1 binds directly to methylated H3K4, facilitating its recruitment to, or stabilization at, DSBs. [Display omitted] •BOD1L, SET1A, and H3K4me3 promote RIF1 accumulation at DNA break sites•SETD1A-dependent H3K4 methylation promotes end-joining and suppresses end-resection•Perturbing SETD1A confers resistance to PARP inhibitors in BRCA1-deficient cells•RIF1 binds directly to methylated H3K4 Bayley et al. identify histone H3K4 methylation by SETD1A as vital for DNA repair, by promoting RIF1 accumulation at damaged sites. Deficiencies in H3 methylation or the SETD1A-BOD1L complex impairs end-joining of broken DNA ends, abrogates class switch recombination, promotes uncontrolled end-resection, and compromises the efficacy of PARP inhibitors.