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首页> 外文期刊>EMBO Journal >Codanin-1, mutated in the anaemic disease CDAI, regulates Asf1 function in S-phase histone supply
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Codanin-1, mutated in the anaemic disease CDAI, regulates Asf1 function in S-phase histone supply

机译：贫血疾病CDAI Codanin-1,突变,组蛋白调节Asf1函数s阶段供应

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摘要

Efficient supply of new histones during DNA replication is critical to restore chromatin organization and maintain genome function. The histone chaperone anti-silencing function 1 (Asf1) serves a key function in providing H3.1-H4 to CAF-1 for replication-coupled nucleosome assembly. We identify Codanin-1 as a novel interaction partner of Asf1 regulating S-phase histone supply. Mutations in Codanin-1 can cause congenital dyserythropoietic anaemia type I (CDAI), characterized by chromatin abnormalities in bone marrow erythroblasts. Codanin-1 is part of a cytosolic Asf1-H3.1-H4-Importin-4 complex and binds directly to Asf1 via a conserved B-domain, implying a mutually exclusive interaction with the chaperones CAF-1 and HIRA. Codanin-1 depletion accelerates the rate of DNA replication and increases the level of chromatin-bound Asf1, suggesting that Codanin-1 guards a limiting step in chromatin replication. Consistently, ectopic Codanin-1 expression arrests S-phase progression by sequestering Asf1 in the cytoplasm, blocking histone delivery. We propose that Codanin-1 acts as a negative regulator of Asf1 function in chromatin assembly. This function is compromised by two CDAI mutations that impair complex formation with Asf1, providing insight into the molecular basis for CDAI disease.
机译：新的组蛋白在DNA的有效供应复制恢复染色质是至关重要的组织和维持基因组的功能。组蛋白伴侣anti-silencing函数1(Asf1)服务提供H3.1-H4关键功能为replication-coupled CAF-1核小体组装。互动的合作伙伴Asf1调节s阶段组蛋白供应。先天性dyserythropoietic贫血类型(CDAI),以染色质异常骨髓成红血球细胞。的胞质Asf1-H3.1-H4-Importin-4复杂并将直接绑定Asf1通过守恒的B-domain,这意味着一个互斥的与监护人的交互CAF-1和希拉。Codanin-1损耗加速DNA复制和增加的程度chromatin-bound Asf1,表明Codanin-1警卫染色质的限制步骤复制。一致,异位Codanin-1表达式逮捕扣押Asf1 s阶段发展在细胞质中,阻断组蛋白交付。建议Codanin-1充当消极监管机构Asf1函数的染色质组装。这个函数是由两个CDAI妥协突变影响复杂的形成Asf1,提供深入的分子基础CDAI疾病。

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