title: BRPF3-HBO1 regulates replication origin activation and histone H3K14 acetylation.
abstract: During DNA replication, thousands of replication origins are activated across the genome. Chromatin architecture contributes to origin specification and usage, yet it remains unclear which chromatin features impact on DNA replication. Here, we perform a RNAi screen for chromatin regulators implicated in replication control by measuring RPA accumulation upon replication stress. We identify six factors required for normal rates of DNA replication and characterize a function of the bromodomain and PHD finger-containing protein 3 (BRPF3) in replication initiation. BRPF3 forms a complex with HBO1 that specifically acetylates histone H3K14, and genomewide analysis shows high enrichment of BRPF3, HBO1 and H3K14ac at ORC1-binding sites and replication origins found in the vicinity of TSSs. Consistent with this, BRPF3 is necessary for H3K14ac at selected origins and efficient origin activation. CDC45 recruitment, but not MCM2-7 loading, is impaired in BRPF3-depleted cells, identifying a BRPF3-dependent function of HBO1 in origin activation that is complementary to its role in licencing. We thus propose that BRPF3-HBO1 acetylation of histone H3K14 around TSS facilitates efficient activation of nearby replication origins.
authors.affiliation: Biotech Research and Innovation Centre (BRIC) and Center for Epigenetics, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Yunpeng
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Biotech Research and Innovation Centre (BRIC) and Center for Epigenetics, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Arsenios
authors.initials: A
authors.lastname: Vlassis
authors.affiliation: St-Patrick Research Group in Basic Oncology, Laval University Cancer Research Center, Oncology Axis-CHU de Québec Research Center, Quebec City, QC, Canada.
authors.forename: Céline
authors.initials: C
authors.lastname: Roques
authors.affiliation: St-Patrick Research Group in Basic Oncology, Laval University Cancer Research Center, Oncology Axis-CHU de Québec Research Center, Quebec City, QC, Canada.
authors.forename: Marie-Eve
authors.initials: ME
authors.lastname: Lalonde
authors.affiliation: Biotech Research and Innovation Centre (BRIC) and Center for Epigenetics, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Cristina
authors.initials: C
authors.lastname: González-Aguilera
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Lambert
authors.affiliation: Biotech Research and Innovation Centre (BRIC) and Center for Epigenetics, University of Copenhagen, Copenhagen, Denmark Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy, Taipei Medical University, Taipei, Taiwan.
authors.forename: Sung-Bau
authors.initials: SB
authors.lastname: Lee
authors.affiliation: Bioinformatics Centre Department of Biology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Xiaobei
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Biotech Research and Innovation Centre (BRIC) and Center for Epigenetics, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Constance
authors.initials: C
authors.lastname: Alabert
authors.affiliation: Biotech Research and Innovation Centre (BRIC) and Center for Epigenetics, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jens V
authors.initials: JV
authors.lastname: Johansen
authors.affiliation: St-Patrick Research Group in Basic Oncology, Laval University Cancer Research Center, Oncology Axis-CHU de Québec Research Center, Quebec City, QC, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Paquet
authors.affiliation: Department of Medicine, McGill University Health Center, Montréal, QC, Canada.
authors.forename: Xiang-Jiao
authors.initials: XJ
authors.lastname: Yang
authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
authors.forename: Anne-Claude
authors.initials: AC
authors.lastname: Gingras
authors.affiliation: St-Patrick Research Group in Basic Oncology, Laval University Cancer Research Center, Oncology Axis-CHU de Québec Research Center, Quebec City, QC, Canada jacques.cote@crhdq.ulaval.ca anja.groth@bric.ku.dk.
authors.forename: Jacques
authors.initials: J
authors.lastname: Côté
authors.affiliation: Biotech Research and Innovation Centre (BRIC) and Center for Epigenetics, University of Copenhagen, Copenhagen, Denmark jacques.cote@crhdq.ulaval.ca anja.groth@bric.ku.dk.
authors.forename: Anja
authors.initials: A
authors.lastname: Groth
mesh_terms: D000107:Acetylation; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D004261:DNA Replication / Q000235:genetics / Q000502:physiology; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D018741:Replication Origin / Q000235:genetics / Q000502:physiology*
chemical_list: D002843:Chromatin; D006657:Histones; D051548:Histone Acetyltransferases; C496553:KAT7 protein, human
keywords: BRPF; DNA replication; H3K14ac; HBO1; origin activation