Chromatin unfolding by Cdt1 regulates MCM loading via opposing functions of HBO1 and HDAC11-geminin
Chromatin unfolding by Cdt1 regulates MCM loading via opposing functions of HBO1 and HDAC11-geminin
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DOI：
10.4161/cc.9.21.13596
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发表时间：
2010-11-01
期刊：
影响因子：
4.3
通讯作者：
Alexandrow, Mark G.
中科院分区：
文献类型：
--
作者：
Wong, Philip G.;Glozak, Michele A.;Alexandrow, Mark G.
已知后生动物DNA复制起点的效率通过在起点附近的组蛋白乙酰化而增强。虽然这与增加MCM招聘，这种乙酰化调节MCM加载的机制是未知的。我们在这里表明，Cdt 1诱导大规模的染色质去凝聚，这是MCM招聘所需的。这一过程发生在G（1）中，被Geminin抑制，需要HBO 1 HAT活性和组蛋白H4修饰。HDAC 11，结合Cdt 1和复制起点在S期，强效抑制Cdt 1诱导的染色质展开和再复制，抑制MCM加载和结合Cdt 1更有效地在存在的Geminin。我们还证明，在内源性来源的染色质是更容易在G（1）相对于S期。这些结果提供了组蛋白乙酰化通过增强染色质可及性促进MCM加载的证据。这一过程受G（1）期Cdt 1和HBO 1的正调控，并受S期与Cdt 1结合的Geminin-HDAC 11的抑制，代表了一种新的复制许可控制形式。
The efficiency of metazoan origins of DNA replication is known to be enhanced by histone acetylation near origins. Although this correlates with increased MCM recruitment, the mechanism by which such acetylation regulates MCM loading is unknown. We show here that Cdt1 induces large-scale chromatin decondensation that is required for MCM recruitment. This process occurs in G(1), is suppressed by Geminin, and requires HBO1 HAT activity and histone H4 modifications. HDAC11, which binds Cdt1 and replication origins during S-phase, potently inhibits Cdt1-induced chromatin unfolding and re-replication, suppresses MCM loading and binds Cdt1 more efficiently in the presence of Geminin. We also demonstrate that chromatin at endogenous origins is more accessible in G(1) relative to S-phase. These results provide evidence that histone acetylation promotes MCM loading via enhanced chromatin accessibility. This process is regulated positively by Cdt1 and HBO1 in G(1) and repressed by Geminin-HDAC11 association with Cdt1 in S-phase, and represents a novel form of replication licensing control.