BRPF3-HBO1 regulates replication origin activation and histone H3K14 acetylation
BRPF3-HBO1 regulates replication origin activation and histone H3K14 acetylation
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DOI：
10.15252/embj.201591293
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发表时间：
2016-01-01
期刊：
影响因子：
11.4
通讯作者：
Groth, Anja
中科院分区：
文献类型：
--
作者：
Feng, Yunpeng;Vlassis, Arsenios;Groth, Anja
在DNA复制过程中，成千上万的复制起点在整个基因组中被激活。染色质结构有助于起源规范和使用，但仍不清楚哪些染色质特征影响DNA复制。在这里，我们通过测量复制应激时RPA的积累来进行涉及复制控制的染色质调节剂的RNAi筛选。我们确定了正常的DNA复制率所需的六个因素，并表征了溴结构域和PHD指蛋白3（BRPF 3）在复制起始中的功能。BRPF 3与HBO 1形成复合物，其特异性乙酰化组蛋白H3 K14，并且全基因组分析显示BRPF 3、HBO 1和H3 K14 ac在TSS附近发现的ORC 1结合位点和复制起点处高度富集。与此一致，BRPF 3是H3 K14 ac在选定的起源和有效的起源激活所必需的。CDC 45募集，但不是MCM 2 -7加载，在BRPF 3耗尽的细胞中受损，鉴定了HBO 1在起源激活中的BRPF 3依赖性功能，其在许可中的作用是互补的。因此，我们提出，组蛋白H3 K14周围TSS的BRPF 3-HBO 1乙酰化促进附近的复制起点的有效激活。
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.