title: The TIP60 Complex Regulates Bivalent Chromatin Recognition by 53BP1 through Direct H4K20me Binding and H2AK15 Acetylation.
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.
authors.affiliation: 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.
authors.forename: Karine
authors.initials: K
authors.lastname: Jacquet
authors.affiliation: 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.
authors.forename: Amélie
authors.initials: A
authors.lastname: Fradet-Turcotte
authors.affiliation: 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.
authors.forename: Nikita
authors.initials: N
authors.lastname: Avvakumov
authors.affiliation: The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Lambert
authors.affiliation: 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.
authors.forename: Céline
authors.initials: C
authors.lastname: Roques
authors.affiliation: Department of Radiation Oncology, The Houston Methodist Research Institute, Houston, TX 77030, USA.
authors.forename: Raj K
authors.initials: RK
authors.lastname: Pandita
authors.affiliation: 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.
authors.forename: Eric
authors.initials: E
authors.lastname: Paquet
authors.affiliation: 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.
authors.forename: Pauline
authors.initials: P
authors.lastname: Herst
authors.affiliation: 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.
authors.forename: Anne-Claude
authors.initials: AC
authors.lastname: Gingras
authors.affiliation: Department of Radiation Oncology, The Houston Methodist Research Institute, Houston, TX 77030, USA.
authors.forename: Tej K
authors.initials: TK
authors.lastname: Pandita
authors.affiliation: 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.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Legube
authors.affiliation: Centre Hospitalier Universitaire de Québec Research Center and School of Medicine, Laval University, Quebec City, QC G1V 4G2, Canada.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Doyon
authors.affiliation: 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.
authors.forename: Daniel
authors.initials: D
authors.lastname: Durocher
authors.affiliation: 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.
authors.forename: Jacques
authors.initials: J
authors.lastname: Côté
mesh_terms: D000107:Acetylation; D001665:Binding Sites; D001667:Binding, Competitive; D064113:CRISPR-Cas Systems; D042002:Chromatin Assembly and Disassembly; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D000074443:Lysine Acetyltransferase 5; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D000071857:Tumor Suppressor p53-Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D002868:Chromosomal Proteins, Non-Histone; C485469:EPC1 protein, human; D006657:Histones; C546112:MBTD1 protein, human; D012097:Repressor Proteins; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5
keywords: 53BP1; H2AK15; H4K20; MBTD1; NuA4; TIP60; acetylation; histone methylation; homologous recombination; ubiquitylation