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

Karine Jacquet, Amélie Fradet-Turcotte, Nikita Avvakumov, Jean Philippe Lambert, Céline Roques, Raj K. Pandita, Eric Paquet, Pauline Herst, Anne Claude Gingras, Tej K. Pandita, Gaëlle Legube, Yannick Doyon, Daniel Durocher, Jacques Côté

Research output: Contribution to journalArticle

95 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)409-421
Number of pages13
JournalMolecular Cell
Volume62
Issue number3
DOIs
StatePublished - May 5 2016

Keywords

  • 53BP1
  • Acetylation
  • H2AK15
  • H4K20
  • Histone methylation
  • Homologous recombination
  • MBTD1
  • NuA4
  • TIP60
  • Ubiquitylation

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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