Palou Gloria, Palou Roger, Zeng Fanli, Vashisht Ajay A, Wohlschlegel James A, Quintana David G
Department of Biochemistry and Molecular Biology, Biophysics Unit, School of Medicine, Universitat Autonoma de Barcelona, Bellaterra, Catalonia, Spain.
Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, California, United States of America.
PLoS Genet. 2015 Sep 2;11(9):e1005468. doi: 10.1371/journal.pgen.1005468. eCollection 2015 Sep.
A surveillance mechanism, the S phase checkpoint, blocks progression into mitosis in response to DNA damage and replication stress. Segregation of damaged or incompletely replicated chromosomes results in genomic instability. In humans, the S phase checkpoint has been shown to constitute an anti-cancer barrier. Inhibition of mitotic cyclin dependent kinase (M-CDK) activity by Wee1 kinases is critical to block mitosis in some organisms. However, such mechanism is dispensable in the response to genotoxic stress in the model eukaryotic organism Saccharomyces cerevisiae. We show here that the Wee1 ortholog Swe1 does indeed inhibit M-CDK activity and chromosome segregation in response to genotoxic insults. Swe1 dispensability in budding yeast is the result of a redundant control of M-CDK activity by the checkpoint kinase Rad53. In addition, our results indicate that Swe1 is an effector of the checkpoint central kinase Mec1. When checkpoint control on M-CDK and on Pds1/securin stabilization are abrogated, cells undergo aberrant chromosome segregation.
一种监测机制，即S期检查点，可响应DNA损伤和复制应激，阻止细胞进入有丝分裂。受损或未完全复制的染色体分离会导致基因组不稳定。在人类中，S期检查点已被证明构成一道抗癌屏障。在某些生物体中，Wee1激酶抑制有丝分裂周期蛋白依赖性激酶（M-CDK）的活性对于阻止有丝分裂至关重要。然而，在模式真核生物酿酒酵母对基因毒性应激的反应中，这种机制是可有可无的。我们在此表明，Wee1直系同源物Swe1确实会响应基因毒性损伤而抑制M-CDK活性和染色体分离。芽殖酵母中Swe1的可有可无性是检查点激酶Rad53对M-CDK活性进行冗余控制的结果。此外，我们的结果表明Swe1是检查点中心激酶Mec1的效应器。当对M-CDK和Pds1/分离酶稳定性的检查点控制被取消时，细胞会发生异常的染色体分离。
