2. Academic Validation
  3. The TIP60 Complex Regulates Bivalent Chromatin Recognition by 53BP1 through Direct H4K20me Binding and H2AK15 Acetylation

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.
Karine Jacquet 1,  Amélie Fradet-Turcotte 2,  Nikita Avvakumov 1,  Jean-Philippe Lambert 3,  Céline Roques 1,  Raj K Pandita 4,  Eric Paquet 1,  Pauline Herst 1,  Anne-Claude Gingras 5,  Tej K Pandita 4,  Gaëlle Legube 6,  Yannick Doyon 7,  Daniel Durocher 5,  Jacques Côté 8
Affiliations

Affiliations

  • 1 St. Patrick Research Group in Basic Oncology, Laval University Cancer Research Center, Quebec City, QC G1R 3S3, Canada; Centre Hospitalier Universitaire de Québec Research Center and School of Medicine, Laval University, Quebec City, QC G1V 4G2, Canada.
  • 2 St. Patrick Research Group in Basic Oncology, Laval University Cancer Research Center, Quebec City, QC G1R 3S3, Canada; Centre Hospitalier Universitaire de Québec Research Center and School of Medicine, Laval University, Quebec City, QC G1V 4G2, Canada; The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
  • 3 The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
  • 4 Department of Radiation Oncology, The Houston Methodist Research Institute, Houston, TX 77030, USA.
  • 5 The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • 6 Laboratoire de Biologie Cellulaire et Moléculaire du Contrôle de la Prolifération (LBCMCP), Centre de Biologie Intégrative (CBI), Université de Toulouse, Centre National de la Recherche Scientifique (CNRS), UPS, 31062 Toulouse, France.
  • 7 Centre Hospitalier Universitaire de Québec Research Center and School of Medicine, Laval University, Quebec City, QC G1V 4G2, Canada.
  • 8 St. Patrick Research Group in Basic Oncology, Laval University Cancer Research Center, Quebec City, QC G1R 3S3, Canada; Centre Hospitalier Universitaire de Québec Research Center and School of Medicine, Laval University, Quebec City, QC G1V 4G2, Canada. Electronic address: jacques.cote@crhdq.ulaval.ca.
PMID: 27153538 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.

Figures