Replication Checkpoint Enforced by Kinases Cds1 and Chk1

Abstract

Cdc2, the kinase that induces mitosis, is regulated by checkpoints that couple mitosis to the completion of DNA replication and repair. The repair checkpoint kinase Chk1 regulates Cdc25, a phosphatase that activates Cdc2. Effectors of the replication checkpoint evoked by hydroxyurea (HU) are unknown. Treatment of fission yeast with HU stimulated the kinase Cds1, which appears to phosphorylate the kinase Wee1, an inhibitor of Cdc2. The protein kinase Cds1 was also required for a large HU-induced increase in the amount of Mik1, a second inhibitor of Cdc2. HU-induced arrest of cell division was abolished in cds1 chk1 cells. Thus, Cds1 and Chk1 appear to jointly enforce the replication checkpoint.

Regulation of mitosis in response to damaged or incompletely replicated DNA require different levels of Grapes (DrosophilaChk1)

“…The differential importance of a Chk1 homolog to these two different responses has been compared only in fission yeast previously. In fission yeast, Chk1 is essential for delaying the entry into mitosis in response to IR damage, but has a redundant, non-essential role in delaying the entry into mitosis in response to incomplete DNA synthesis (Boddy et al, 1998;Brondello et al, 1999;Walworth and Bernards, 1996). Our results suggest a reverse situation in fly embryos; the regulation of mitotic progress after irradiation still occurs when levels of Grp are too low to support the regulation of mitosis in the presence of incomplete DNA replication.…”

The bacterial cytolethal distending toxin (CDT) triggers a G2 cell cycle checkpoint in mammalian cells without preliminary induction of DNA strand breaks

“…These observations could mean that CDT induces a G2 checkpoint control that is normally activated during S phase, such as a replication checkpoint. The replication checkpoint couples mitosis to completion of DNA replication and maintains CDK1 in an inactive phosphorylated form (Boddy et al, 1998). In this regard, there might be some analogy between the mode of action of CDT and that of a viral protein, the Vpr of human immunode®ciency virus (HIV-1), which induces a G2 block in HeLa cells through inactivation of CDK1 by hyperphosphorylation (Poon et al, 1997a).…”

Cdc25C interacts with PCNA at G2/M transition

“…It is known that Chk1 is activated by the damaged DNA in ®ssion yeast (Walworth et al, 1993;al-Khodairy et al, 1994;Walworth and Bernards, 1996). It is also known that ®ssion yeast Cds1 (Boddy et al, 1998;Zeng et al, 1998;Lindsay et al, 1997) and budding yeast Rad (Weinert et al, 1994;Allen et al, 1994;Paulovich and Hartwell, 1995) are activated by the unreplicated DNA and presumably by the damaged DNA. It appears that there is redundancy between the function of Cds1 and Chk1, since abrogation of DNA damage checkpoint requires disruption of not only Chk1 but also Cds1 in ®ssion yeast (Boddy et al, 1998;Zeng et al, 1998;O'Connell et al, 1997).…”

“…It is also known that ®ssion yeast Cds1 (Boddy et al, 1998;Zeng et al, 1998;Lindsay et al, 1997) and budding yeast Rad (Weinert et al, 1994;Allen et al, 1994;Paulovich and Hartwell, 1995) are activated by the unreplicated DNA and presumably by the damaged DNA. It appears that there is redundancy between the function of Cds1 and Chk1, since abrogation of DNA damage checkpoint requires disruption of not only Chk1 but also Cds1 in ®ssion yeast (Boddy et al, 1998;Zeng et al, 1998;O'Connell et al, 1997). The dual phosphatase Cdc25 triggers MPF by reversing the Wee1-mediated phosphorylation of Cdc2 (Parker and Piwnica-Worms, 1992;Russell and Nurse, 1986).…”

“…The dual phosphatase Cdc25 triggers MPF by reversing the Wee1-mediated phosphorylation of Cdc2 (Parker and Piwnica-Worms, 1992;Russell and Nurse, 1986). Both Chk1 and Cds1 can not only activate Wee1 (Boddy et al, 1998;O'Connell et al, 1997) but also directly suppress Cdc25 by phosphorylation at serine 216 (Zeng et al, 1998;Blasina et al, 1999;Lopez-Girona et al, 1999), thus inhibiting the cell cycle progression by MPF. The phosphorylated Cdc25 is sequestrated in the cytoplasm by association with 14-3-3 (Lopez-Girona et al, 1999).…”