The TIP60 Complex Regulates Bivalent Chromatin Recognition by 53BP1 Through Direct H4K20me Binding and H2AK15 Acetylation

Mol Cell. 2016 May 5;62(3):409-421. doi: 10.1016/j.molcel.2016.03.031.

Abstract

The NuA4/TIP60 acetyltransferase complex is a key regulator of genome expression and stability. Here we identified MBTD1 as a stable subunit of the complex, and we reveal that, via a histone reader domain for H4K20me1/2, MBTD1 allows TIP60 to associate with specific gene promoters and to promote the repair of DNA double-strand breaks by homologous recombination. It was previously suggested that TIP60-dependent acetylation of H4 regulates binding of the non-homologous end joining factor 53BP1, which engages chromatin through simultaneous binding of H4K20me2 and H2AK15ub. We find that the TIP60 complex regulates association of 53BP1 partly by competing for H4K20me2 and by regulating H2AK15ub. Ubiquitylation of H2AK15 by RNF168 inhibits chromatin acetylation by TIP60, while this residue can be acetylated by TIP60 in vivo, blocking its ubiquitylation. Altogether, these results uncover an intricate mechanism orchestrated by the TIP60 complex to regulate 53BP1-dependent repair through competitive bivalent binding and modification of chromatin.

Keywords: 53BP1; H2AK15; H4K20; MBTD1; NuA4; TIP60; acetylation; histone methylation; homologous recombination; ubiquitylation.

Publication types

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

MeSH terms

  • Acetylation
  • Binding Sites
  • Binding, Competitive
  • CRISPR-Cas Systems
  • Chromatin Assembly and Disassembly*
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism*
  • DNA Breaks, Double-Stranded
  • DNA Repair
  • Histone Acetyltransferases / genetics
  • Histone Acetyltransferases / metabolism*
  • Histones / genetics
  • Histones / metabolism*
  • Humans
  • K562 Cells
  • Lysine Acetyltransferase 5
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Processing, Post-Translational*
  • RNA Interference
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Signal Transduction
  • Time Factors
  • Transcription, Genetic
  • Transfection
  • Tumor Suppressor p53-Binding Protein 1 / genetics
  • Tumor Suppressor p53-Binding Protein 1 / metabolism*
  • Ubiquitination

Substances

  • Chromosomal Proteins, Non-Histone
  • EPC1 protein, human
  • Histones
  • MBTD1 protein, human
  • Repressor Proteins
  • TP53BP1 protein, human
  • Tumor Suppressor p53-Binding Protein 1
  • Histone Acetyltransferases
  • KAT5 protein, human
  • Lysine Acetyltransferase 5