Chk1 is a histone H3 threonine 11 kinase that regulates DNA damage-induced transcriptional repression
Chk1 is a histone H3 threonine 11 kinase that regulates DNA damage-induced transcriptional repression
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DOI：
10.1016/j.cell.2007.12.013
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发表时间：
2008-01-25
期刊：
影响因子：
64.5
通讯作者：
Nakanishi, Makoto
中科院分区：
文献类型：
--
作者：
Shimada, Midori;Niida, Hiroyuki;Nakanishi, Makoto
DNA损伤导致大量基因转录的激活或抑制。在序列特异性dna结合激活剂的背景下，转录激活已被很好地表征，而转录抑制的机制在很大程度上尚未被探索。我们在这里表明，DNA损伤迅速降低组蛋白H3苏氨酸11 （T11）磷酸化。这与细胞周期蛋白B1和cdk1等基因的抑制有关。H3-T11磷酸化发生在整个细胞周期中，并且在体内依赖于Chk1。DNA损伤后，Chk1经历快速的染色质解离，伴随H3-T11磷酸化降低。此外，我们发现H3-T11磷酸化的缺失与组蛋白乙酰转移酶GCN5在细胞周期蛋白B1和cdk1启动子上的结合减少以及H3-K9乙酰化的减少有关。我们提出了Chk1作为一种组蛋白激酶的机制，通过组蛋白乙酰化的丧失，负责dna损伤诱导的转录抑制。
DNA damage results in activation or suppression of transcription of a large number of genes. Transcriptional activation has been well characterized in the context of sequence-specific DNA-bound activators, whereas mechanisms of transcriptional suppression are largely unexplored. We show here that DNA damage rapidly reduces histone H3 Threonine 11 (T11) phosphorylation. This correlates with repression of genes, including cyclin B1 and cdk1. H3-T11 phosphorylation occurs throughout the cell cycle and is Chk1 dependent in vivo. Following DNA damage, Chk1 undergoes rapid chromatin dissociation, concomitant with reduced H3-T11 phosphorylation. Furthermore, we find that loss of H3-T11 phosphorylation correlates with reduced binding of the histone acetyltransferase GCN5 at cyclin B1 and cdk1 promoters and reduced H3-K9 acetylation. We propose a mechanism for Chk1 as a histone kinase, responsible for DNA-damage-induced transcriptional repression by loss of histone acetylation.