Codanin-1, mutated in the anaemic disease CDAI, regulates Asf1 function in S-phase histone supply
Codanin-1, mutated in the anaemic disease CDAI, regulates Asf1 function in S-phase histone supply
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DOI：
10.1038/emboj.2012.55
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发表时间：
2012-04-18
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：
Ask, Katrine;Jasencakova, Zuzana;Groth, Anja
在DNA复制过程中，新组蛋白的有效供应对于恢复染色质组织和维持基因组功能至关重要。组蛋白伴侣抗沉默功能1（Asf 1）在向CAF-1提供H3.1-H4以用于复制偶联核小体组装中起关键作用。我们确定Codanin-1作为一种新的相互作用的合作伙伴Asf 1调节S-相组蛋白供应。Codanin-1突变可导致先天性红细胞生成不良性贫血I型（CDAI），其特征为骨髓成红细胞染色质异常。Codanin-1是胞质Asf 1-H3.1-H4-Importin-4复合物的一部分，并通过保守的B结构域直接与Asf 1结合，这意味着与伴侣CAF-1和HIRA相互排斥的相互作用。Codanin-1耗竭加速了DNA复制的速率并增加了染色质结合的Asf 1的水平，表明Codanin-1保护了染色质复制中的限制步骤。一致地，异位Codanin-1表达通过在细胞质中隔离Asf 1，阻断组蛋白递送来阻止S期进展。我们建议Codanin-1作为一个负调节Asf 1功能的染色质组装。这一功能受到两个CDAI突变的损害，这两个突变损害了与Asf 1的复合物形成，从而为CDAI疾病的分子基础提供了深入了解。EMBO期刊（2012）31，2013-2023。doi：10.1038/2012.55;在线发布9三月2012主题分类：染色质和转录;基因组稳定性和动力学;疾病的分子生物学
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. The EMBO Journal (2012) 31, 2013-2023. doi:10.1038/emboj.2012.55; Published online 9 March 2012 Subject Categories: chromatin & transcription; genome stability & dynamics; molecular biology of disease