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通过与Crb2的动态相互作用对检查点激酶的调控。

Regulation of checkpoint kinases through dynamic interaction with Crb2.

作者信息

Mochida Satoru, Esashi Fumiko, Aono Nobuki, Tamai Katsuyuki, O'Connell Matthew J, Yanagida Mitsuhiro

机构信息

Graduate School of Biostudies, Kyoto University, Kitashirakawa-Oiwakecho, Sakyo-ku, Kyoto, Japan.

出版信息

EMBO J. 2004 Jan 28;23(2):418-28. doi: 10.1038/sj.emboj.7600018. Epub 2004 Jan 22.

Abstract

ATR/Rad3-like kinases promote the DNA damage checkpoint through regulating Chk1 that restrains the activation of cyclin-dependent kinases. In fission yeast, Crb2, a BRCT-domain protein that is similar to vertebrate 53BP1, plays a crucial role in establishing this checkpoint. We report here that Crb2 regulates DNA damage checkpoint through temporal and dynamic interactions with Rad3, Chk1 and replication factor Cut5. The active complex formation between Chk1 and Crb2 is regulated by Rad3 and became maximal during the checkpoint arrest. Chk1 activation seems to need two steps of interaction changes: the loss of Rad3-Chk1 and Rad3-Crb2 interactions, and the association between hyperphosphorylated forms of Chk1 and Crb2. Chk1 is the major checkpoint kinase for the arrest of DNA polymerase mutants. The in vitro assay of Chk1 showed that its activation requires the presence of Crb2 BRCT. Hyperphosphorylation of Crb2 is also dependent on its intact BRCT. Finally, we show direct interaction between Rad3 and Crb2, which is inhibitory to Rad3 activity. Hence, Crb2 is the first to interact with both Rad3 and Chk1 kinases.

摘要

ATR/Rad3样激酶通过调控Chk1来促进DNA损伤检查点,而Chk1会抑制细胞周期蛋白依赖性激酶的激活。在裂殖酵母中,Crb2是一种与脊椎动物53BP1相似的含BRCT结构域的蛋白质,在建立该检查点中起关键作用。我们在此报告,Crb2通过与Rad3、Chk1和复制因子Cut5进行时间和动态相互作用来调控DNA损伤检查点。Chk1与Crb2之间的活性复合物形成受Rad3调控,并在检查点停滞期间达到最大值。Chk1的激活似乎需要两步相互作用变化:Rad3 - Chk1和Rad3 - Crb2相互作用的丧失,以及Chk1和Crb2的超磷酸化形式之间的结合。Chk1是使DNA聚合酶突变体停滞的主要检查点激酶。Chk1的体外实验表明其激活需要Crb2的BRCT结构域存在。Crb2的超磷酸化也依赖于其完整的BRCT结构域。最后,我们展示了Rad3与Crb2之间的直接相互作用,这对Rad3活性具有抑制作用。因此,Crb2是第一个同时与Rad3和Chk1激酶相互作用的蛋白。

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