Human SIRT1 regulates DNA binding and stability of the Mcm10 DNA replication factor via deacetylation.
Human SIRT1 regulates DNA binding and stability of the Mcm10 DNA replication factor via deacetylation.
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DOI：
10.1093/nar/gkt131
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发表时间：
2013-04
影响因子：
14.9
通讯作者：
Okorokov AL
中科院分区：
文献类型：
--
作者：
Fatoba ST;Tognetti S;Berto M;Leo E;Mulvey CM;Godovac-Zimmermann J;Pommier Y;Okorokov AL
真核DNA复制起始因子Mcm10对复制体的组装和功能都是必不可少的。人Mcm10有两个DNA结合域，保守的内部结构域(ID)和后生动物特有的C末端结构域(CTD)。SIRT1是一种依赖于烟酰胺腺嘌呤二核苷酸(NAD)的脱乙酰酶，属于sirtuin家族。它从酵母到人类都是保守的，参与了新陈代谢、寿命、基因表达和基因组稳定性的细胞控制。在此，我们报道了人Mcm10是一种受SIRT1调控的乙酰化蛋白，它在体内和体外都能结合和去乙酰化Mcm10，并调节Mcm10的稳定性和结合DNA的能力。Mcm10和SIRT1似乎协同作用于DNA复制分叉的启动。此外，我们还发现Mcm10的两个DNA结合域受到乙酰化/去乙酰化的不同方式的调节，这表明了一个完整的调控机制。总体而言，我们的研究强调了蛋白质乙酰化对DNA复制启动和进展的重要性，并表明SIRT1可能介导了控制新陈代谢的细胞回路和DNA合成之间的串扰。
The eukaryotic DNA replication initiation factor Mcm10 is essential for both replisome assembly and function. Human Mcm10 has two DNA-binding domains, the conserved internal domain (ID) and the C-terminal domain (CTD), which is specific to metazoans. SIRT1 is a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase that belongs to the sirtuin family. It is conserved from yeast to human and participates in cellular controls of metabolism, longevity, gene expression and genomic stability. Here we report that human Mcm10 is an acetylated protein regulated by SIRT1, which binds and deacetylates Mcm10 both in vivo and in vitro, and modulates Mcm10 stability and ability to bind DNA. Mcm10 and SIRT1 appear to act synergistically for DNA replication fork initiation. Furthermore, we show that the two DNA-binding domains of Mcm10 are modulated in distinct fashion by acetylation/deacetylation, suggesting an integrated regulation mechanism. Overall, our study highlights the importance of protein acetylation for DNA replication initiation and progression, and suggests that SIRT1 may mediate a crosstalk between cellular circuits controlling metabolism and DNA synthesis.
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