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首页> 外文期刊>Molecular and Cellular Biology >Xenopus Cds1 Is Regulated by DNA-Dependent Protein Kinase and ATR during the Cell Cycle Checkpoint Response to Double-Stranded DNA Ends
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Xenopus Cds1 Is Regulated by DNA-Dependent Protein Kinase and ATR during the Cell Cycle Checkpoint Response to Double-Stranded DNA Ends

机译：非洲爪蟾Cds1受DNA依赖性蛋白激酶和ATR在细胞周期检查点对双链DNA末端的反应期间。

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The checkpoint kinase Cds1 (Chk2) plays a key role in cell cycle checkpoint responses with functions in cell cycle arrest, DNA repair, and induction of apoptosis. Proper regulation of Cds1 is essential for appropriate cellular responses to checkpoint-inducing insults. While the kinase ATM has been shown to be important in the regulation of human Cds1 (hCds1), here we report that the kinases ATR and DNA-dependent protein kinase (DNA-PK) play more significant roles in the regulation of Xenopus Cds1 (XCds1). Under normal cell cycle conditions, nonactivated XCds1 constitutively associates with a Xenopus ATR complex. The association of XCds1 with this complex does not require a functional forkhead activation domain but does require a putative SH3 binding region that is found in XCds1. In response to double-stranded DNA ends, the amino terminus of XCds1 is rapidly phosphorylated in a sequential pattern. First DNA-PK phosphorylates serine 39, a site not previously recognized as important in Cds1 regulation. Xenopus ATM, ATR, and/or DNA-PK then phosphorylate three consensus serine/glutamine sites. Together, these phosphorylations have the dual function of inducing dissociation from the ATR complex and independently promoting the full activation of XCds1. Thus, the checkpoint-mediated activation of XCds1 requires phosphorylation by multiple phosphoinositide 3-kinase-related kinases, protein-protein dissociation, and autophosphorylation.
机译：检查点激酶Cds1（Chk2）在细胞周期检查点反应中起关键作用，在细胞周期停滞，DNA修复和凋亡诱导中起作用。 Cds1的正确调节对于适当的细胞对检查点诱导的损伤的反应至关重要。虽然已证明激酶ATM在调节人Cds1（hCds1）中很重要，但在此我们报道激酶ATR和DNA依赖性蛋白激酶（DNA-PK）在非洲爪蟾的调节中起着更重要的作用。 Cds1（XCds1）。在正常细胞周期条件下，未激活的XCds1与非洲爪蟾 ATR复合体组成性结合。 XCds1与该复合物的关联不需要功能性的叉头激活域，但需要在XCds1中找到的推定的SH3结合区。响应双链DNA末端，XCds1的氨基末端以连续模式快速磷酸化。首先，DNA-PK使丝氨酸39磷酸化，这是以前在Cds1调控中不重要的位点。然后，非洲爪蟾 ATM，ATR和/或DNA-PK磷酸化三个共有的丝氨酸/谷氨酰胺位点。这些磷酸化一起具有诱导从ATR复合物中解离并独立促进XCds1完全活化的双重功能。因此，XCds1的检查点介导的激活需要多个磷酸肌醇3激酶相关激酶的磷酸化，蛋白质-蛋白质的解离和自磷酸化。

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