title: Src family kinases promote silencing of ATR-Chk1 signaling in termination of DNA damage checkpoint.
abstract: The DNA damage checkpoint arrests cell cycle progression to allow time for repair. Once DNA repair is completed, checkpoint signaling is terminated. Currently little is known about the mechanism by which checkpoint signaling is terminated, and the disappearance of DNA lesions is considered to induce the end of checkpoint signaling; however, here we show that the termination of checkpoint signaling is an active process promoted by Src family tyrosine kinases. Inhibition of Src activity delays recovery from the G2 phase DNA damage checkpoint following DNA repair. Src activity is required for the termination of checkpoint signaling, and inhibition of Src activity induces persistent activation of ataxia telangiectasia mutated (ATM)- and Rad3-related (ATR) and Chk1 kinases. Src-dependent nuclear protein tyrosine phosphorylation and v-Src expression suppress the ATR-mediated Chk1 and Rad17 phosphorylation induced by DNA double strand breaks or DNA replication stress. Thus, Src family kinases promote checkpoint recovery through termination of ATR- and Chk1-dependent G2 DNA damage checkpoint. These results suggest a model according to which Src family kinases send a termination signal between the completion of DNA repair and the initiation of checkpoint termination.
authors.affiliation: From the Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan and.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Fukumoto
authors.forename: Mariko
authors.initials: M
authors.lastname: Morii
authors.forename: Takahito
authors.initials: T
authors.lastname: Miura
authors.forename: Sho
authors.initials: S
authors.lastname: Kubota
authors.forename: Kenichi
authors.initials: K
authors.lastname: Ishibashi
authors.forename: Takuya
authors.initials: T
authors.lastname: Honda
authors.forename: Aya
authors.initials: A
authors.lastname: Okamoto
authors.forename: Noritaka
authors.initials: N
authors.lastname: Yamaguchi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Iwama
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nakayama
authors.forename: Naoto
authors.initials: N
authors.lastname: Yamaguchi
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D004260:DNA Repair; D015536:Down-Regulation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D005434:Flow Cytometry; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008856:Microscopy, Fluorescence; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D007211:Indoles; D009687:Nuclear Proteins; C113575:Rad17 protein, human; C416927:SU 6656; D013449:Sulfonamides; D059005:Topoisomerase II Inhibitors; D014443:Tyrosine; D004317:Doxorubicin; D011494:Protein Kinases; D019061:src-Family Kinases; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1
keywords: Cell Cycle; Checkpoint Control; Checkpoint Recovery; DNA Damage; DNA Damage Response; Src