| First Author | Kan Q | Year | 2008 |
| Journal | J Biol Chem | Volume | 283 |
| Issue | 26 | Pages | 17864-72 |
| PubMed ID | 18458079 | Mgi Jnum | J:138120 |
| Mgi Id | MGI:3804333 | Doi | 10.1074/jbc.M802055200 |
| Citation | Kan Q, et al. (2008) Cdc6 determines utilization of p21(WAF1/CIP1)-dependent damage checkpoint in S phase cells. J Biol Chem 283(26):17864-72 |
| abstractText | When cells traversing G(1) are irradiated with UV light, two parallel damage checkpoint pathways are activated: Chk1-Cdc25A and p53-p21(WAF1/CIP1), both targeting Cdk2, but the latter inducing a long lasting arrest. In similarly treated S phase-progressing cells, however, only the Cdc25A-dependent checkpoint is active. We have recently found that the p21-dependent checkpoint can be activated and induce a prolonged arrest if S phase cells are damaged with a base-modifying agent, such as methyl methanesulfonate (MMS) and cisplatin. But the mechanistic basis for the differential activation of the p21-dependent checkpoint by different DNA damaging agents is not understood. Here we report that treatment of S phase cells with MMS but not a comparable dose of UV light elicits proteasome-mediated degradation of Cdc6, the assembler of pre-replicative complexes, which allows induced p21 to bind Cdk2, thereby extending inactivation of Cdk2 and S phase arrest. Consistently, enforced expression of Cdc6 largely eliminates the prolonged S phase arrest and Cdk2 inactivation induced with MMS, whereas RNA interference-mediated Cdc6 knockdown not only prolongs such arrest and inactivation but also effectively activates the p21-dependent checkpoint in the UV-irradiated S phase cells. |
