title: Lyn tyrosine kinase promotes silencing of ATM-dependent checkpoint signaling during recovery from DNA double-strand breaks.
abstract: DNA damage activates the DNA damage checkpoint and the DNA repair machinery. After initial activation of DNA damage responses, cells recover to their original states through completion of DNA repair and termination of checkpoint signaling. Currently, little is known about the process by which cells recover from the DNA damage checkpoint, a process called checkpoint recovery. Here, we show that Src family kinases promote inactivation of ataxia telangiectasia mutated (ATM)-dependent checkpoint signaling during recovery from DNA double-strand breaks. Inhibition of Src activity increased ATM-dependent phosphorylation of Chk2 and Kap1. Src inhibition increased ATM signaling both in G2 phase and during asynchronous growth. shRNA knockdown of Lyn increased ATM signaling. Src-dependent nuclear tyrosine phosphorylation suppressed ATM-mediated Kap1 phosphorylation. These results suggest that Src family kinases are involved in upstream signaling that leads to inactivation of the ATM-dependent DNA damage checkpoint.
authors.affiliation: Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan. Electronic address: fukumoto@faculty.chiba-u.jp.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Fukumoto
authors.affiliation: Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan.
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Kuki
authors.affiliation: Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Morii
authors.affiliation: Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan.
authors.forename: Takahito
authors.initials: T
authors.lastname: Miura
authors.affiliation: Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Honda
authors.affiliation: Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Ishibashi
authors.affiliation: Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Hasegawa
authors.affiliation: Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Kubota
authors.affiliation: Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan.
authors.forename: Yudai
authors.initials: Y
authors.lastname: Ide
authors.affiliation: Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan.
authors.forename: Noritaka
authors.initials: N
authors.lastname: Yamaguchi
authors.affiliation: Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nakayama
authors.affiliation: Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan. Electronic address: nyama@faculty.chiba-u.jp.
authors.forename: Naoto
authors.initials: N
authors.lastname: Yamaguchi
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics*; D064447:Checkpoint Kinase 2 / Q000235:genetics / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology; D000076183:Tripartite Motif-Containing Protein 28; D019061:src-Family Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: C468783:H2AX protein, human; D006657:Histones; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D059005:Topoisomerase II Inhibitors; D004317:Doxorubicin; C101116:TRIM28 protein, human; D000076183:Tripartite Motif-Containing Protein 28; D064447:Checkpoint Kinase 2; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human
keywords: Cell cycle; Checkpoint control; Checkpoint recovery; DNA damage; DNA damage response; Src