Luciano Pierre, Dehé Pierre-Marie, Audebert Stéphane, Géli Vincent, Corda Yves
Ligue Nationale Contre le Cancer (Équipe Labellisée), Marseille Cancer Research Center, U1068 Institut National de la Santé et de la Recherche Médicale, UMR7258 Centre National de la Recherche Scientifique, UM105 Aix-Marseille University, Institut Paoli-Calmettes, Marseille, F-13009, France.
Ligue Nationale Contre le Cancer (Équipe Labellisée), Marseille Cancer Research Center, U1068 Institut National de la Santé et de la Recherche Médicale, UMR7258 Centre National de la Recherche Scientifique, UM105 Aix-Marseille University, Institut Paoli-Calmettes, Marseille, F-13009, France
Genetics. 2015 Apr;199(4):1047-63. doi: 10.1534/genetics.114.173856. Epub 2015 Feb 18.
Histone H3 lysine 56 acetylation in Saccharomyces cerevisiae is required for the maintenance of genome stability under normal conditions and upon DNA replication stress. Here we show that in the absence of H3 lysine 56 acetylation replisome components become deleterious when replication forks collapse at natural replication block sites. This lethality is not a direct consequence of chromatin assembly defects during replication fork progression. Rather, our genetic analyses suggest that in the presence of replicative stress H3 lysine 56 acetylation uncouples the Cdc45-Mcm2-7-GINS DNA helicase complex and DNA polymerases through the replisome component Ctf4. In addition, we discovered that the N-terminal domain of Ctf4, necessary for the interaction of Ctf4 with Mms22, an adaptor protein of the Rtt101-Mms1 E3 ubiquitin ligase, is required for the function of the H3 lysine 56 acetylation pathway, suggesting that replicative stress promotes the interaction between Ctf4 and Mms22. Taken together, our results indicate that Ctf4 is an essential member of the H3 lysine 56 acetylation pathway and provide novel mechanistic insights into understanding the role of H3 lysine 56 acetylation in maintaining genome stability upon replication stress.
酿酒酵母中的组蛋白H3赖氨酸56乙酰化在正常条件下以及DNA复制应激时对维持基因组稳定性是必需的。我们在此表明，在缺乏H3赖氨酸56乙酰化的情况下，当复制叉在天然复制阻滞位点坍塌时，复制体成分会变得有害。这种致死性不是复制叉推进过程中染色质组装缺陷的直接后果。相反，我们的遗传学分析表明，在存在复制应激时，H3赖氨酸56乙酰化通过复制体成分Ctf4使Cdc45-Mcm2-7-GINS DNA解旋酶复合体与DNA聚合酶解离。此外，我们发现Ctf4的N端结构域是Ctf4与Mms22相互作用所必需的，Mms22是Rtt101-Mms1 E3泛素连接酶的衔接蛋白，H3赖氨酸56乙酰化途径的功能需要该结构域，这表明复制应激促进了Ctf4与Mms22之间的相互作用。综上所述，我们的结果表明Ctf4是H3赖氨酸56乙酰化途径的重要成员，并为理解H3赖氨酸56乙酰化在复制应激时维持基因组稳定性中的作用提供了新的机制见解。
