title: The interaction between checkpoint kinase 1 (Chk1) and the minichromosome maintenance (MCM) complex is required for DNA damage-induced Chk1 phosphorylation.
abstract: Chk1 is an essential mediator of the DNA damage response and cell cycle checkpoint. However, how exactly Chk1 transduces the checkpoint signaling is not fully understood. Here we report the identification of the heterohexamic minichromosome maintenance (MCM) complex that interacts with Chk1 by mass spectrometry. The interaction between Chk1 and the MCM complex was reduced by DNA damage treatment. We show that the MCM complex, at least partially, contributes to the chromatin association of Chk1, allowing for immediate phosphorylation of Chk1 by ataxia telangiectasia mutated and Rad3-related (ATR) in the presence of DNA damage. Further, phosphorylation of Chk1 at ATR sites reduces the interaction between Chk1 and the MCM complex, facilitating chromatin release of phosphorylated Chk1, a critical step in the initiation and amplification of cell cycle checkpoint. Together, these data provide novel insights into the activation of Chk1 in response to DNA damage.
authors: From the Department of Pharmacology, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio 44106.
authors: Xiangzi
authors: X
authors: Han
authors: the Molecular and Cellular Biology Laboratories, The Salk Institute, La Jolla, California 92037, and.
authors: Aaron
authors: A
authors: Aslanian
authors: From the Department of Pharmacology, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio 44106.
authors: Kang
authors: K
authors: Fu
authors: Celgene Corporation, San Diego, California 92121.
authors: Toshiya
authors: T
authors: Tsuji
authors: From the Department of Pharmacology, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio 44106, yxz169@case.edu.
authors: Youwei
authors: Y
authors: Zhang
mesh_terms: D002460:Cell Line; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D006801:Humans; D064110:Minichromosome Maintenance Proteins / Q000378:metabolism*; D018384:Oxidative Stress; D010766:Phosphorylation; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism*
chemical_list: D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D064110:Minichromosome Maintenance Proteins
keywords: Checkpoint Control; DNA Damage; DNA Damage Response; Molecular Biology; Signal Transduction