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Abstract
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.
Original language | English |
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Pages (from-to) | 1924-1939.e10 |
Number of pages | 26 |
Journal | Molecular Cell |
Volume | 82 |
Issue number | 10 |
Early online date | 18 Apr 2022 |
DOIs | |
Publication status | Published - 19 May 2022 |
Bibliographical note
Funding Information:We thank Clare Davies, Jo Morris, and other members of the Birmingham Centre for Genome Biology (BCGB) for invaluable discussions. We are grateful to Robert Klose for providing KDM5A expression reagents and Graham Dellaire for providing plasmids for the CRISPR-based HR assay. We thank the Crick BRF and GEMs for support with animal production and experiments. R.B. was funded by a Birmingham Fellowship and a Wellcome Institutional Strategic Support Fund (204846/Z/16/Z) awarded to M.R.H. by the University of Birmingham. E.S. is funded by the University of Birmingham and supported by Cancer Research UK (C17422/A25154). R.M.A.M. was funded by the UK Medical Research Council and University of Birmingham. M.R.H. A.O. and A.G. are funded by a UK Medical Research Council Career Development Fellowship (MR/P009085/1). M.S. is supported by a Birmingham Fellowship, the Wellcome Trust (202115/Z/16/Z), Royal Society (RG170246), and BBSRC (BB/S016155/1). G.S.S. is funded by a CR-UK Programme Grant (C17183/A23303). S.J.B. P.R. T.S. and V.B. are supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC0010048), the UK Medical Research Council (FC0010048), and the Wellcome Trust (FC0010048). S.J.B. is also funded by a European Research Council (ERC) Advanced Investigator Grant (TelMetab) and Wellcome Trust Senior Investigator and Collaborative Grants. Conceptualization, M.R.H. G.S.S. and S.J.B.; investigation, R.B. V.B. R.J.M. E.S. P.R. A.O. A.G. R.M.A.M. M.S. G.S.S. and M.R.H.; resources, T.S. and G.H.; writing—original draft, R.B. V.B. S.J.B. and M.R.H. with comments from all authors; writing—review & editing, M.R.H. S.J.B. and R.B.; funding acquisition, M.R.H. G.S.S. and S.J.B.; supervision, M.R.H. G.S.S. and S.J.B. S.J.B. is a co-founder and VP in Science Strategy at Artios Pharma and is a member of the Molecular Cell advisory board. The authors declare no other competing interests.
Publisher Copyright:
© 2022 The Author(s)
Keywords
- double-strand break repair
- 53BP1
- RIF1
- shieldin
- SETD1A
- H3K4 methylation
- BOD1L
- class switch recombination
- PARP inhibitors
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology
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