Checkpoint kinase 1 in DNA damage response and cell cycle regulation
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Cellular and Molecular Life Sciences
Review
Checkpoint kinase 1 in DNA damage response and cell cycle regulation Mallikarjun Patil · Navjotsingh Pabla · Zheng Dong
Received: 6 November 2012 / Revised: 28 January 2013 / Accepted: 18 February 2013 © Springer Basel 2013
Abstract Originally identified as a mediator of DNA damage response (DDR), checkpoint kinase 1 (Chk1) has a broader role in checkpoint activation in DDR and normal cell cycle regulation. Chk1 activation involves phosphorylation at conserved sites. However, recent work has identified a splice variant of Chk1, which may regulate Chk1 in both DDR and normal cell cycle via molecular interaction. Upon activation, Chk1 phosphorylates a variety of substrate proteins, resulting in the activation of DNA damage checkpoints, cell cycle arrest, DNA repair, and/or cell death. Chk1 and its related signaling may be an effective therapeutic target in diseases such as cancer. Keywords Chk1 · Cell cycle · DNA damage · Checkpoint Abbreviations Chk1 Checkpoint kinase 1 Chk2 Checkpoint kinase 2 Chk1 S-checkpoint kinase 1-short DDR DNA damage response ATM Ataxia telangiectasia mutated M. Patil · N. Pabla · Z. Dong Department of Cellular Biology and Anatomy, Georgia Regents University and Charlie Norwood VA Medical Center, 1459 Laney Walker Blvd., Augusta, GA 30912, USA Z. Dong (*) Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha 410022, Hunan, China e-mail: [email protected] Present Address: N. Pabla Department of Pharmaceutical Sciences, St Jude Children’s Research Hospital, Memphis, Tennessee, USA
ATR ATM and Rad3 related Cdc25 Cell division cycle 25 CDK Cyclin-dependent kinases
Introduction Checkpoint kinase 1 (Chk1) was initially identified in fission yeast as a serine/threonine protein kinase that is essential for DNA damage-induced cell cycle arrest [1]. Chk1 homologs were subsequently identified in other species such as Drosophila, Xenopus, mouse, and human [2–4]. Functional studies in these model systems showed that Chk1 phosphorylates the key regulators of cyclin-dependent kinase 1 (CDK1) during DNA damage, resulting in CDK1 inactivation and blockade of G2/M transition. More recent work has established important roles of Chk1 not only in DNA damage response (DDR) but also in unperturbed cell cycle. In the normal cell cycle, Chk1 mediates the checkpoints in S and M phases as well as G2/M transition. In this review, we discuss Chk1 regulation, its role in DDR and unperturbed cell cycle, and the possibility of targeting Chk1 for cancer therapy.
Cell cycle and DNA damage response The cell cycle consists of a series of highly ordered, sequential phases that lead to cell division [5]. A notable feature of cell cycle progression is that cells do not enter the next phase until the previous phase is completed. This feature, known as cell cycle checkpoints, provides an important surveillance mechanism for faithful replication and division of the cells [5] (Fig. 1). Progression from one phase of cell cycle to the next
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