期刊
MOLECULAR CELL
卷 82, 期 10, 页码 1924-+出版社
CELL PRESS
DOI: 10.1016/j.molcel.2022.03.030
关键词
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资金
- Crick BRF - Birmingham Fellowship
- Wellcome Institutional Strategic Support Fund [204846/Z/16/Z]
- University of Birmingham - University of Birmingham
- Cancer Research UK [FC0010048]
- UK Medical Research Council [FC0010048]
- University of Birmingham - UK Medical Research Council Career Development Fellowship [MR/P009085/1]
- Birmingham Fellowship
- Wellcome Trust
- Royal Society [RG170246]
- BBSRC [BB/S016155/1]
- CR-UK Programme Grant [C17183/A23303]
- Francis Crick Institute
- Wellcome Trust - European Research Council (ERC) Advanced Investigator Grant
- BBSRC [BB/S016155/1] Funding Source: UKRI
- Wellcome Trust [204846/Z/16/Z] Funding Source: Wellcome Trust
The study suggests that methylation of histone H3 by SETD1A-BOD1L contributes to the recruitment of RIF1 to double-strand breaks, preventing excessive degradation of DNA ends and maintaining genome stability. This mechanism plays a crucial role in preserving telomere function and class switch recombination, and may be associated with the treatment and resistance of certain cancers.
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 BRCA 1-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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