title: Src family kinases maintain the balance between replication stress and the replication checkpoint.
abstract: Progression of DNA replication is tightly controlled by replication checkpoints to ensure the accurate and rapid duplication of genetic information. Upon replication stress, the replication checkpoint slows global DNA replication by inhibiting the late-firing origins and by slowing replication fork progression. Activation of the replication checkpoint has been studied in depth; however, little is known about the termination of the replication checkpoint. Here, we show that Src family kinases promote the recovery from replication checkpoints. shRNA knockdown of a Src family kinase, Lyn, and acute chemical inhibition of Src kinases prevented inactivation of Chk1 after removal of replication stress. Consistently, Src inhibition slowed resumption of DNA replication, after the removal of replication blocks. The effect of Src inhibition was not observed in the presence of an ATM/ATR inhibitor caffeine. These data indicate that Src kinases promote the resumption of DNA replication by suppressing ATR-dependent replication checkpoints. Surprisingly, the resumption of replication was delayed by caffeine. In addition, Src inhibition delayed recovery from replication fork collapse. We propose that Src kinases maintain the balance between replication stress and the activity of the replication checkpoint.
authors.affiliation: Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Inohana 1-8-1, Chuo-ku, 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, Inohana 1-8-1, Chuo-ku, Chiba , 260-8675, Japan.
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Fukumoto
authors.affiliation: Department of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Inohana 1-8-1, Chuo-ku, 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, Inohana 1-8-1, Chuo-ku, 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, Inohana 1-8-1, Chuo-ku, 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, Inohana 1-8-1, Chuo-ku, 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, Inohana 1-8-1, Chuo-ku, Chiba , 260-8675, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Yamaguchi
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002110:Caffeine / Q000494:pharmacology; D018929:Cell Culture Techniques; D059447:Cell Cycle Checkpoints / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D000071877:Checkpoint Kinase 1 / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D015398:Signal Transduction; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D002110:Caffeine; D019061:src-Family Kinases; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1
keywords: ATR; Chk1; DNA replication checkpoint; Src family kinases; checkpoint recovery