Chk1 suppressed cell death
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REVIEW
Open Access
Chk1 suppressed cell death Mark Meuth Abstract The role of Chk1 in the cellular response to DNA replication stress is well established. However recent work indicates a novel role for Chk1 in the suppression of apoptosis following the disruption of DNA replication or DNA damage. This review will consider these findings in the context of known pathways of Chk1 signalling and potential applications of therapies that target Chk1. Review The orderly and accurate replication of DNA is essential for the maintenance of genetic stability in cells. Cell cycle checkpoints play a critical role in this process by sensing DNA damage or aberrant replication structures and then slowing entry into S-phase, progression through S-phase, and mitosis to facilitate repair [1]. Recent work from a number of laboratories shows that some of these checkpoint responses regulate apoptosis in response to disruptions of DNA replication. Cell death helps maintain genetic stability by eliminating damaged cells that are not likely to be repaired. Thus a balance between cell cycle arrest and repair and the induction of cell death that is determined by checkpoints is critical for the preservation of genetic integrity. p53 plays a major role in the induction of apoptosis through the transcriptional activation of proapoptotic genes such as BAX and PUMA in response to DNA damage [2-4]. Thus in tumour cells deficient in p53 the balance between cell death and cell cycle arrest/repair is compromised. If repair is incomplete or inaccurate, genetic abnormalities may accumulate in p53-deficient tumour cells in part because cells acquiring DNA damage are no longer committed to death. Recently a number of laboratories using very different approaches have attempted to restore apoptotic responses in tumour cells to make them more responsive to therapeutic agents. Intriguingly several of these efforts have become focused on the checkpoint kinase, Chk1, as being particularly critical for the control of apoptosis in tumour cells. Here I will review recent work implicating
Correspondence: [email protected] Institute for Cancer Studies, University of Sheffield, School of Medicine and Biomedical Sciences, Sheffield S10 2RX, UK
Chk1 as a key mediator of death in tumour cells in response to the disruption of DNA replication. The ATR-Chk1 pathway primarily responds to ssDNA generated by DNA replication stress
Chk1 is critical to a wide range of responses to DNA replication stress and some forms of DNA damage. Chk1 is rapidly phosphorylated at several sites in an Ataxia telangiectasia mutated and Rad3 related (ATR)dependent manner after inhibition of DNA replication [5]. These post translational modifications are required to trigger cell cycle checkpoints in S and G2 [6], suppress inappropriate firing of late or cryptic DNA replication origins [7], and maintain replication fork integrity [8,9]. The roles of Chk1 in cell cycle checkpoints overlap with those of another DNA damage response pathway controlled by the Ataxia telangiectasia mutated (
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