| First Author | Bayley R | Year | 2022 |
| Journal | Mol Cell | Volume | 82 |
| Issue | 10 | Pages | 1924-1939.e10 |
| PubMed ID | 35439434 | Mgi Jnum | J:337726 |
| Mgi Id | MGI:7286111 | Doi | 10.1016/j.molcel.2022.03.030 |
| Citation | Bayley R, et al. (2022) H3K4 methylation by SETD1A/BOD1L facilitates RIF1-dependent NHEJ. Mol Cell 82(10):1924-1939.e10 |
| abstractText | 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. |
