A human Cds1-related kinase that functions downstream of ATM protein in the cellular response to DNA damage

Checkpoints maintain the order and fidelity of the eukaryotic cell cycle, a nd defects in checkpoints contribute to genetic instability and cancer. Muc h of our current understanding of checkpoints comes from genetic studies co nducted in yeast. In the fission yeast Schizosaccharomyces pombe (Sp), SpRa d3 is an essential component of both the DNA damage and DNA replication che ckpoints. The SpChk1 and SpCds1 protein kinases function downstream of SpRa d3. 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 d amage checkpoint, Human homologs of both SpRad3 and SpChk1 but not SpCds1 h ave been identified. Here we report the identification of a human cDNA enco ding a protein (designated HuCds1) that shares sequence, structural, and fu nctional similarity to SpCds1, HuCds1 was modified by phosphorylation and a ctivated in response to ionizing radiation. It was also modified in respons e 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 pro mote the binding of 14-3-3 proteins. These findings suggest that the checkp oint function of HuCds1 is conserved in yeast and mammals.