Cdc7 Is an Active Kinase in Human Cancer Cells Undergoing Replication Stress

Cdc7 kinase mediates Claspin phosphorylation in DNA replication checkpoint

“…Terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) analysis revealed that an increased proportion of Cdc7 siRNA-treated cells underwent cell death upon HU treatment (Figure 2b). Hypersensitivity to HU has also been reported for budding yeast cdc7 ts and fission yeast hsk1 ts strains (Takeda et al, 1999;Weinreich and Stillman, 1999;Matsumoto et al, 2005), and recently for Cdc7-depleted human cancer cell lines (Tenca et al, 2007). Thus, Cdc7-depleted cells have defect in the checkpoint responses to replication fork arrest, which leads to elevated sensitivity to HU treatment.…”

“…In contrast, it has also been demonstrated that the kinase activity of Cdc7 is not affected by a replication block induced by aphidicolin treatment in Xenopus system (Yanow et al, 2003). Moreover, it was recently reported that Cdc7 retains its kinase activity after replication stress in human cells (Tenca et al, 2007). In yeast, in vitro kinase activity of Cdc7 is inhibited by prior phosphorylation by Rad53 (Kihara et al, 2000).…”

“…These observations suggest that the inhibition of Cdc7 activity might be one of the effector mechanisms targeted by replication checkpoint responses. On the other hand, it has also been demonstrated that Cdc7 kinase complex remains active after DNA damages in both Xenopus (Yanow et al, 2003) and humans (Tenca et al, 2007), suggesting its positive role in checkpoint responses. The role for Cdc7 as a mediator of replication checkpoint signaling has also been suggested by the finding that HU-induced activation of Cds1 was significantly impaired in a temperature-sensitive (ts) strain of hsk1 (Takeda et al, 2001).…”

Chk1 promotes replication fork progression by controlling replication initiation

“…Although it is currently not clear whether Chk1 regulates Cdc7 in vivo (20,21), Cdc7 activity is known to promote origin firing. Accordingly, Cdc7 depletion had a similar effect to Cdk inhibition in rescuing replication fork speeds in Chk1-deficient cells (Fig.…”

“…Firstly it inhibits the cyclin-dependent kinase Cdk2 (in complex with Cyclin A or E) by phosphorylation of its activating phosphatase Cdc25A, thus marking Cdc25A for degradation (19). Secondly Chk1 can phosphorylate and inhibit the initiation kinase Cdc7/Dbf4 (Dbf4-dependent kinase, DDK) (20), although it is currently not established that Cdc7 is down-regulated during replication stress (21). Both Cdk2 and Cdc7 phosphorylate the preRC to facilitate loading of the replicative helicase cofactor Cdc45 and thus origin activation (22).…”