Novel protein with similarities to Rb binding protein 2 compensates for loss of Chk1 function and affects histone modification in fission yeast
Novel protein with similarities to Rb binding protein 2 compensates for loss of Chk1 function and affects histone modification in fission yeast
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DOI：
10.1128/mcb.24.9.3660-3669.2004
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发表时间：
2004-05-01
影响因子：
5.3
通讯作者：
Walworth, NC
中科院分区：
文献类型：
--
作者：
Ahmed, S;Palermo, C;Walworth, NC
保守的蛋白激酶Chk1介导细胞周期进程，从而影响细胞在DNA损伤剂作用下的存活能力。缺乏Chk1的细胞对这种药物高度敏感，在DNA受损的情况下进入有丝分裂，而检查点熟练的细胞推迟有丝分裂进入，以便有时间进行DNA修复。在寻找可以提高暴露在DNA损伤中的Chk1缺陷细胞存活的蛋白质的过程中，我们鉴定了分裂酵母Msc1，它与一种与肿瘤抑制因子Rb(RBP2)结合的哺乳动物蛋白同源。Msc1和RBP2各自都有三个PhD手指，这是蛋白质中常见的影响染色质结构的区域。MSC1是染色质相关的，共沉淀组蛋白脱乙酰基酶活性，这一特性需要博士的手指。缺乏Msc1的细胞具有显著改变的组蛋白乙酰化模式，表现出组蛋白H3尾部的整体乙酰化增加20倍，并且很容易被组蛋白去乙酰基酶的抑制剂曲古抑素A杀死。我们推测Msc1在调节染色质结构中起重要作用，并且该功能调节细胞对DNA损伤的反应。
The conserved protein kinase Chk1 mediates cell cycle progression and consequently the ability of cells to survive when exposed to DNA damaging agents. Cells deficient in Chk1 are hypersensitive to such agents and enter mitosis in the presence of damaged DNA, whereas checkpoint-proficient cells delay mitotic entry to permit time for DNA repair. In a search for proteins that can improve the survival of Chk1-deficient cells exposed to DNA damage, we identified fission yeast Msc1, which is homologous to a mammalian protein that binds to the tumor suppressor Rb (RBP2). Msc1 and RBP2 each possess three PHD fingers, domains commonly found in proteins that influence the structure of chromatin. Msc1 is chromatin associated and coprecipitates a histone deacetylase activity, a property that requires the PHD fingers. Cells lacking Msc1 have a dramatically altered histone acetylation pattern, exhibit a 20-fold increase in global acetylation of histone H3 tails, and are readily killed by trichostatin A, an inhibitor of histone deacetylases. We postulate that Msc1 plays an important role in regulating chromatin structure and that this function modulates the cellular response to DNA damage.