A human Cds1-related kinase that functions downstream of ATM protein in the cellular response to DNA damage
A human Cds1-related kinase that functions downstream of ATM protein in the cellular response to DNA damage
复制标题
DOI：
10.1073/pnas.96.7.3745
复制
发表时间：
1999-03-30
影响因子：
11.1
通讯作者：
Chung, JH
中科院分区：
文献类型：
--
作者：
Brown, AL;Lee, CH;Chung, JH
检查点维持着真核细胞周期的秩序和保真度，而检查点的缺陷会导致遗传不稳定和癌症。我们目前对检查点的大部分了解来自于在酵母中进行的基因研究。在裂殖酵母中，SpRad3是DNA损伤和DNA复制检查点的重要组成部分。SpChk1和SpCDs1蛋白激酶在SpRad3下游发挥作用。SpChk1是DNA损伤检查点的效应器，在没有SpCDs1的情况下，它在DNA复制检查点起着至关重要的作用。SpCDs1在DNA复制检查点和S期DNA损伤检查点发挥作用，已经鉴定出SpRad3和SpChk1的人类同源物，但不包括SpCDs1。在这里，我们报告了编码一种与SpCDs1在序列、结构和功能上相似的蛋白质(命名为HuCDs1)的人cDNA，HuCDs1被磷酸化修饰并被电离辐射激活。它也被修饰以响应羟基脲的处理。电离辐射后的HuCDs1修饰需要有功能的ATM蛋白，而羟基脲处理后则不需要。与其裂解酵母类似，人CDS1磷酸化CDC25C以促进14-3-3蛋白的结合。这些发现表明，HuCDs1的检查点功能在酵母和哺乳动物中是保守的。
Checkpoints maintain the order and fidelity of the eukaryotic cell cycle, and defects in checkpoints contribute to genetic instability and cancer. Much of our current understanding of checkpoints comes from genetic studies conducted in yeast. In the fission yeast Schizosaccharomyces pombe (Sp), SpRad3 is an essential component of both the DNA damage and DNA replication checkpoints. The SpChk1 and SpCds1 protein kinases function downstream of SpRad3. SpChk1 is an effector of the DNA damage checkpoint and, in the absence of SpCds1, serves an essential function in the DNA replication checkpoint. SpCds1 functions in the DNA replication checkpoint and in the S phase DNA damage checkpoint, Human homologs of both SpRad3 and SpChk1 but not SpCds1 have been identified. Here we report the identification of a human cDNA encoding a protein (designated HuCds1) that shares sequence, structural, and functional similarity to SpCds1, HuCds1 was modified by phosphorylation and activated in response to ionizing radiation. It was also modified in response to hydroxyurea treatment. Functional ATM protein was required for HuCds1 modification after ionizing radiation but not after hydroxyurea treatment. Like its fission yeast counterpart, human Cds1 phosphorylated Cdc25C to promote the binding of 14-3-3 proteins. These findings suggest that the checkpoint function of HuCds1 is conserved in yeast and mammals.