53BP1 is a reader of the DNA-damage-induced H2A Lys 15 ubiquitin mark

Nature. 2013 Jul 4;499(7456):50-4. doi: 10.1038/nature12318. Epub 2013 Jun 12.

Abstract

53BP1 (also called TP53BP1) is a chromatin-associated factor that promotes immunoglobulin class switching and DNA double-strand-break (DSB) repair by non-homologous end joining. To accomplish its function in DNA repair, 53BP1 accumulates at DSB sites downstream of the RNF168 ubiquitin ligase. How ubiquitin recruits 53BP1 to break sites remains unknown as its relocalization involves recognition of histone H4 Lys 20 (H4K20) methylation by its Tudor domain. Here we elucidate how vertebrate 53BP1 is recruited to the chromatin that flanks DSB sites. We show that 53BP1 recognizes mononucleosomes containing dimethylated H4K20 (H4K20me2) and H2A ubiquitinated on Lys 15 (H2AK15ub), the latter being a product of RNF168 action on chromatin. 53BP1 binds to nucleosomes minimally as a dimer using its previously characterized methyl-lysine-binding Tudor domain and a carboxy-terminal extension, termed the ubiquitination-dependent recruitment (UDR) motif, which interacts with the epitope formed by H2AK15ub and its surrounding residues on the H2A tail. 53BP1 is therefore a bivalent histone modification reader that recognizes a histone 'code' produced by DSB signalling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / metabolism
  • Cell Line
  • Chromosomal Proteins, Non-Histone / chemistry
  • Chromosomal Proteins, Non-Histone / deficiency
  • Chromosomal Proteins, Non-Histone / genetics
  • DNA Breaks, Double-Stranded
  • DNA Damage*
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • Female
  • Histones / chemistry*
  • Histones / metabolism*
  • Humans
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Intracellular Signaling Peptides and Proteins / deficiency
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Lysine / metabolism*
  • Male
  • Mice
  • Molecular Sequence Data
  • Mutant Proteins / chemistry
  • Mutant Proteins / metabolism
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / metabolism
  • Nucleosomes / chemistry
  • Nucleosomes / metabolism
  • Protein Binding
  • Protein Structure, Tertiary
  • Schizosaccharomyces
  • Schizosaccharomyces pombe Proteins / chemistry
  • Schizosaccharomyces pombe Proteins / metabolism
  • Signal Transduction
  • Tumor Suppressor p53-Binding Protein 1
  • Ubiquitin / metabolism*
  • Ubiquitination*

Substances

  • Cell Cycle Proteins
  • Chromosomal Proteins, Non-Histone
  • Crb2 protein, S pombe
  • DNA-Binding Proteins
  • Histones
  • Intracellular Signaling Peptides and Proteins
  • Mutant Proteins
  • Nuclear Proteins
  • Nucleosomes
  • Schizosaccharomyces pombe Proteins
  • Trp53bp1 protein, mouse
  • Tumor Suppressor p53-Binding Protein 1
  • Ubiquitin
  • Lysine