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The most fundamental aspect of cell division is the precise transfer of genetic material to daughter cells. In order to maintain genome stability the daughter cells need to receive an exact copy of the genetic material from the original cell. This is achieved mainly through two processes. First, the genetic material is carefully copied during the process of DNA replication in S phase of the cell cycle, and thereafter it is precisely segregated into two identical daughter cells during mitosis (M phase). Additional control and preparation for DNA replication occurs in G1 phase, which is the gap phase between M and S phases, and DNA repair processes and preparation for mitosis occurs in G2 phase, which is the gap phase between S and M phases. A major obstacle for genome stability is endogenous sources of DNA damage during S phase, which can lead to mutations or chromosome rearrangements if left unrepaired. Such mutations and chromosome rearrangements can again cause cell death or lead to the development of diseases associated with genomic instability such as cancer and neurodegenerative disorders (Jackson and Bartek, 2009). The cellular mechanisms that protect against induction of endogenous DNA damage during S phase are therefore particularly important. DNA replication is tightly regulated by a number of signaling pathways including regulators of Cyclin-Dependent Kinase (CDK) activity. Following exposure to external sources of DNA damage CDK activity is restrained due to activation of the checkpoint kinases Ataxia Telangiactasia-like Rad3 kinase (ATR), Checkpoint kinase 1 (CHK1) and WEE1 kinase (Cliby et al., 1998; Rowley et al., 1992; Sorensen et al., 2003). Importantly, recent work have suggested that proper control of CDK activity by these checkpoint kinases is also required during normal S phase to protect cells against the induction of harmful DNA lesions (Beck et al., 2010; Lam et al., 2004; Syljuasen et al., 2005). In this chapter we review the roles of ATR, CHK1, and WEE1 during normal DNA replication, and discuss their critical function in maintaining genome stability by preventing induction of harmful DNA lesions in S phase. We also discuss the links of ATR, CHK1, and WEE1 with cancer.

Faithful DNA Replication Requires Regulation of CDK Activity by Checkpoint Kinases