title: Mammalian Chk2 is a downstream effector of the ATM-dependent DNA damage checkpoint pathway.
abstract: In response to DNA damage and replication blocks, cells activate pathways that arrest the cell cycle and induce the transcription of genes that facilitate repair. In mammals, ATM (ataxia telangiectasia mutated) kinase together with other checkpoint kinases are important components in this response. We have cloned the rat and human homologs of Saccharomyces cerevisiae Rad 53 and Schizosaccharomyces pombe Cds1, called checkpoint kinase 2 (chk2). Complementation studies suggest that Chk2 can partially replace the function of the defective checkpoint kinase in the Cds1 deficient yeast strain. Chk2 was phosphorylated and activated in response to DNA damage in an ATM dependent manner. Its activation in response to replication blocks by hydroxyurea (HU) treatment, however, was independent of ATM. Using mass spectrometry, we found that, similar to Chk1, Chk2 can phosphorylate serine 216 in Cdc25C, a site known to be involved in negative regulation of Cdc25C. These results suggest that Chk2 is a downstream effector of the ATM-dependent DNA damage checkpoint pathway. Activation of Chk2 might not only delay mitotic entry, but also increase the capacity of cultured cells to survive after treatment with gamma-radiation or with the topoisomerase-I inhibitor topotecan.
authors.affiliation: Department of Oncology Research, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA.
authors.forename: P
authors.initials: P
authors.lastname: Chaturvedi
authors.forename: W K
authors.initials: WK
authors.lastname: Eng
authors.forename: Y
authors.initials: Y
authors.lastname: Zhu
authors.forename: M R
authors.initials: MR
authors.lastname: Mattern
authors.forename: R
authors.initials: R
authors.lastname: Mishra
authors.forename: M R
authors.initials: MR
authors.lastname: Hurle
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: R S
authors.initials: RS
authors.lastname: Annan
authors.forename: Q
authors.initials: Q
authors.lastname: Lu
authors.forename: L F
authors.initials: LF
authors.lastname: Faucette
authors.forename: G F
authors.initials: GF
authors.lastname: Scott
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.forename: S A
authors.initials: SA
authors.lastname: Carr
authors.forename: R K
authors.initials: RK
authors.lastname: Johnson
authors.forename: J D
authors.initials: JD
authors.lastname: Winkler
authors.forename: B B
authors.initials: BB
authors.lastname: Zhou
mesh_terms: D000477:Alkylating Agents / Q000494:pharmacology; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000378:metabolism; D002478:Cells, Cultured; D064447:Checkpoint Kinase 2; D003001:Cloning, Molecular; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics*; D018076:DNA, Complementary / Q000235:genetics; D004271:DNA, Fungal / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D005720:Gamma Rays; D005816:Genetic Complementation Test; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D010766:Phosphorylation; D011494:Protein Kinases; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011506:Proteins / Q000502:physiology*; D051381:Rats; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D012568:Schizosaccharomyces / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D029702:Schizosaccharomyces pombe Proteins; D015398:Signal Transduction; D013045:Species Specificity; D059004:Topoisomerase I Inhibitors; D019772:Topotecan / Q000494:pharmacology; D025521:Tumor Suppressor Proteins; D020666:ras-GRF1
chemical_list: D000477:Alkylating Agents; D018797:Cell Cycle Proteins; D018076:DNA, Complementary; D004271:DNA, Fungal; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D005656:Fungal Proteins; D011506:Proteins; D029702:Schizosaccharomyces pombe Proteins; D059004:Topoisomerase I Inhibitors; D025521:Tumor Suppressor Proteins; D020666:ras-GRF1; D019772:Topotecan; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human; C578636:Cds1 protein, S pombe; C578632:Chek2 protein, rat; D017346:Protein Serine-Threonine Kinases; D006918:Hydroxyurea