Three Different Pathways Prevent Chromosome Segregation in the Presence of DNA Damage or Replication Stress in Budding Yeast.
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.
Department of Biochemistry and Molecular Biology, Biophysics Unit, School of Medicine, Universitat Autonoma de Barcelona, Bellaterra, Catalonia, Spain.
Gloria
G
Palou
Department of Biochemistry and Molecular Biology, Biophysics Unit, School of Medicine, Universitat Autonoma de Barcelona, Bellaterra, Catalonia, Spain.
Roger
R
Palou
Department of Biochemistry and Molecular Biology, Biophysics Unit, School of Medicine, Universitat Autonoma de Barcelona, Bellaterra, Catalonia, Spain.
Fanli
F
Zeng
Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, California, United States of America.
Ajay A
AA
Vashisht
Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, California, United States of America.
James A
JA
Wohlschlegel
Department of Biochemistry and Molecular Biology, Biophysics Unit, School of Medicine, Universitat Autonoma de Barcelona, Bellaterra, Catalonia, Spain.
David G
DG
Quintana
D020090:Chromosome Segregation; D015825:Chromosomes, Fungal; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004249:DNA Damage; D004261:DNA Replication; D009153:Mutagens / Q000633:toxicity; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism
D009153:Mutagens; D029701:Saccharomyces cerevisiae Proteins; D018844:Cyclin-Dependent Kinases