Open AccessA human Cds1-related kinase that functions downstream of ATM protein in the cellular response to DNA damage
Author(s) -
Alexandra L. Brown,
Chang-Hun Lee,
Julie K. Schwarz,
Nesanet Mitiku,
Helen PiwnicaWorms,
Jay H. Chung
Publication year - 1999
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.96.7.3745
Subject(s) - g2 m dna damage checkpoint , schizosaccharomyces pombe , dna damage , biology , chek1 , dna repair , dna replication , checkpoint kinase 2 , dna re replication , microbiology and biotechnology , cell cycle checkpoint , eukaryotic dna replication , control of chromosome duplication , dna pkcs , origin recognition complex , replication protein a , dna , genetics , cell cycle , saccharomyces cerevisiae , dna binding protein , yeast , gene , transcription factor
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 yeastSchizosaccharomyces 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.