BRPF3‐HBO1 regulates replication origin activation and histone H3K14 acetylation |
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| Authors: | Marie‐Eve Lalonde Cristina González‐Aguilera Jean‐Philippe Lambert Sung‐Bau Lee Xiaobei Zhao Constance Alabert Jens V Johansen Eric Paquet Xiang‐Jiao Yang Anne‐Claude Gingras Jacques Côté Anja Groth |
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| Institution: | 1. St‐Patrick Research Group in Basic Oncology, Laval University Cancer Research Center, Oncology Axis‐CHU de Québec Research Center, Quebec City, QC, Canada;2. Biotech Research and Innovation Centre (BRIC) and Center for Epigenetics, University of Copenhagen, Copenhagen, Denmark;3. Lunenfeld‐Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada;4. 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. Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada |
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| 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. |
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| Keywords: | BRPF DNA replication HBO1 H3K14ac origin activation |
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