共 13 条
Polo-like kinase-1 controls proteasome-dependent degradation of claspin during checkpoint recovery
被引:173
作者:
Mamely, Ivan
van Vugt, Marcel A. T. M.
Smits, Veronique A. J.
Semple, Jennifer I.
Lemmens, Bennie
Perrakis, Anastassis
Medema, Rene H.
Freire, Raimundo
机构:
[1] Univ Utrecht, Med Ctr, Dept Med Oncol, NL-3584 CG Utrecht, Netherlands
[2] Hosp Univ Canarias, Unidad Invest, Tenerife 38320, Spain
[3] Erasmus MC, Dept Cell Biol & Genet, NL-3000 DR Rotterdam, Netherlands
[4] Netherlands Canc Inst, Div Mol Carcinogenesis, NL-1066 CX Amsterdam, Netherlands
关键词:
D O I:
10.1016/j.cub.2006.08.026
中图分类号:
Q5 [生物化学];
Q7 [分子生物学];
学科分类号:
071010 ;
081704 ;
摘要:
DNA-damage checkpoints maintain genomic integrity by mediating a cell-cycle delay in response to genotoxic stress or stalled replication forks. In response to damage, the checkpoint kinase ATR phosphorylates and activates its effector kinase Chk1 in a process that critically depends on Claspin [1]. However, it is not known how exactly this kinase cascade is silenced. Here we demonstrate that the abundance of Claspin is regulated through proteasomal degradation. In response to DNA damage, Claspin is transiently stabilized, and its expression depends on Chk1 kinase activity. In addition, we show that Claspin is degraded upon mitotic entry, a process that depends on the beta-TrCP-SCF ubiquitin ligase and Polo-like kinase-1 (Plk1). We demonstrate that Claspin interacts with both beta-TrCP and Plk1 and that inactivation of these components or the beta-TrCP recognition motif in Claspin prevents its mitotic degradation. Interestingly, expression of a nondegradable Claspin mutant inhibits recovery from a DNA-damage-induced checkpoint arrest. Thus, we conclude that Claspin levels are tightly regulated, both during unperturbed cell cycles and after DNA damage. Moreover, our data demonstrate that the degradation of Claspin at the onset of mitosis is an essential step for the recovery of a cell from a DNA-damage-induced cell-cycle arrest.
引用
收藏
页码:1950 / 1955
页数:6
相关论文