Chk1是一种组蛋白H3苏氨酸11激酶，可调节DNA损伤诱导的转录抑制。

Chk1 is a histone H3 threonine 11 kinase that regulates DNA damage-induced transcriptional repression.

作者信息

Shimada Midori, Niida Hiroyuki, Zineldeen Doaa H, Tagami Hideaki, Tanaka Masafumi, Saito Hiroyuki, Nakanishi Makoto

机构信息

Department of Cell Biology and Biochemistry, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.

出版信息

Cell. 2008 Jan 25;132(2):221-32. doi: 10.1016/j.cell.2007.12.013.

DOI:10.1016/j.cell.2007.12.013

PMID:18243098

Abstract

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.

摘要

DNA损伤会导致大量基因转录的激活或抑制。转录激活在序列特异性DNA结合激活因子的背景下已得到充分表征，而转录抑制机制在很大程度上尚未被探索。我们在此表明，DNA损伤会迅速降低组蛋白H3苏氨酸11（T11）的磷酸化水平。这与包括细胞周期蛋白B1和细胞周期蛋白依赖性激酶1（cdk1）在内的基因的抑制相关。H3-T11磷酸化在整个细胞周期中都会发生，并且在体内依赖于Chk1。DNA损伤后，Chk1会迅速从染色质上解离，同时H3-T11磷酸化水平降低。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启动子处的结合减少以及H3-K9乙酰化水平降低相关。我们提出了一种Chk1作为组蛋白激酶的机制，其通过组蛋白乙酰化的缺失导致DNA损伤诱导的转录抑制。