H3K4 methylation by SETD1A/BOD1L facilitates RIF1-dependent NHEJ
2022
Bayley, Rachel | Borel, Valerie | Moss, Rhiannon J. | Sweatman, Ellie | Ruis, Philip | Ormrod, Alice | Goula, Amalia | Mottram, Rachel M.A. | Stanage, Tyler | Hewitt, Graeme | Saponaro, Marco | Stewart, Grant S. | Boulton, Simon J. | Higgs, Martin R.
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.
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