BRPF3-HBO1 regulates replication origin activation and histone H3K14 acetylation

EMBO J. 2016 Jan 18;35(2):176-92. doi: 10.15252/embj.201591293.

Yunpeng Feng ¹, Arsenios Vlassis ¹, Céline Roques ², Marie-Eve Lalonde ², Cristina González-Aguilera ¹, Jean-Philippe Lambert ³, Sung-Bau Lee ⁴, Xiaobei Zhao ⁵, Constance Alabert ¹, Jens V Johansen ¹, Eric Paquet ², Xiang-Jiao Yang ⁶, Anne-Claude Gingras ⁷, Jacques Côté ⁸, Anja Groth ⁹

Affiliations

1 Biotech Research and Innovation Centre (BRIC) and Center for Epigenetics, University of Copenhagen, Copenhagen, Denmark.
2 St-Patrick Research Group in Basic Oncology, Laval University Cancer Research Center, Oncology Axis-CHU de Québec Research Center, Quebec City, QC, Canada.
3 Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
4 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.
5 Bioinformatics Centre Department of Biology, University of Copenhagen, Copenhagen, Denmark.
6 Department of Medicine, McGill University Health Center, Montréal, QC, Canada.
7 Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
8 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.
9 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.

PMID: 26620551 DOI: 10.15252/embj.201591293

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.

Keywords

BRPF; DNA replication; H3K14ac; HBO1; origin activation.

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