TIRR regulates 53BP1 by masking its histone methyl-lysine binding function

Nature. 2017 Mar 9;543(7644):211-216. doi: 10.1038/nature21358. Epub 2017 Feb 27.


P53-binding protein 1 (53BP1) is a multi-functional double-strand break repair protein that is essential for class switch recombination in B lymphocytes and for sensitizing BRCA1-deficient tumours to poly-ADP-ribose polymerase-1 (PARP) inhibitors. Central to all 53BP1 activities is its recruitment to double-strand breaks via the interaction of the tandem Tudor domain with dimethylated lysine 20 of histone H4 (H4K20me2). Here we identify an uncharacterized protein, Tudor interacting repair regulator (TIRR), that directly binds the tandem Tudor domain and masks its H4K20me2 binding motif. Upon DNA damage, the protein kinase ataxia-telangiectasia mutated (ATM) phosphorylates 53BP1 and recruits RAP1-interacting factor 1 (RIF1) to dissociate the 53BP1-TIRR complex. However, overexpression of TIRR impedes 53BP1 function by blocking its localization to double-strand breaks. Depletion of TIRR destabilizes 53BP1 in the nuclear-soluble fraction and alters the double-strand break-induced protein complex centring 53BP1. These findings identify TIRR as a new factor that influences double-strand break repair using a unique mechanism of masking the histone methyl-lysine binding function of 53BP1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • Binding Sites
  • Carrier Proteins / metabolism*
  • DNA Breaks, Double-Stranded
  • DNA Repair
  • Female
  • Histones / chemistry*
  • Histones / metabolism*
  • Humans
  • Lysine / metabolism*
  • Methylation
  • Mice
  • Mice, Inbred C57BL
  • Phosphorylation
  • Protein Binding
  • Protein Domains
  • RNA-Binding Proteins
  • Telomere-Binding Proteins / metabolism
  • Tumor Suppressor p53-Binding Protein 1 / antagonists & inhibitors*
  • Tumor Suppressor p53-Binding Protein 1 / chemistry
  • Tumor Suppressor p53-Binding Protein 1 / metabolism*


  • Carrier Proteins
  • Histones
  • NUDT16L1 protein, human
  • RNA-Binding Proteins
  • Rif1 protein, human
  • TP53BP1 protein, human
  • Telomere-Binding Proteins
  • Tumor Suppressor p53-Binding Protein 1
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Lysine