H3K4 methylation by SETD1A/BOD1L facilitates RIF1-dependent NHEJ

Rachel Bayley, Valerie Borel, Rhiannon J Moss, Ellie Sweatman, Philip Ruis, Alice Ormrod, Amalia Goula, Rachel M A Mottram, Tyler Stanage, Graeme Hewitt, Marco Saponaro, Grant S Stewart, Simon J Boulton, Martin R Higgs

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)

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 languageEnglish
Pages (from-to)1924-1939.e10
JournalMOLECULAR CELL
Volume82
Issue number10
DOIs
Publication statusPublished - 19 May 2022

Keywords

  • BRCA1 Protein/genetics
  • DNA/metabolism
  • DNA Breaks, Double-Stranded
  • DNA End-Joining Repair
  • DNA Repair
  • Histone-Lysine N-Methyltransferase/genetics
  • Humans
  • Methylation
  • Telomere-Binding Proteins/genetics
  • Tumor Suppressor p53-Binding Protein 1/genetics

Fingerprint

Dive into the research topics of 'H3K4 methylation by SETD1A/BOD1L facilitates RIF1-dependent NHEJ'. Together they form a unique fingerprint.

Cite this