Abstract
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.
Highlights
Cells are continuously exposed to spontaneous DNA damage
To start dissecting how budding yeast cells block mitosis, we explored whether mitotic cyclin dependent kinase (M-CDK) activity is downregulated in response to genotoxic stress
Identical results were obtained when replication was instead challenged by DNA damage (S3 Fig). These results indicate that the S phase checkpoint downregulates M-CDK activity in response to genotoxic stress in Saccharomyces cerevisiae
Summary
Cells are continuously exposed to spontaneous DNA damage. Proliferating cells are vulnerable during chromosome replication in S phase. Replication forks stall as a result of shortage of deoxynucleotides (replication stress), or the presence of DNA lesions that block the progression of the replisome [1,2]. In eukaryotic cells a surveillance mechanism, the S phase checkpoint, is activated by stalled replication forks. The checkpoint blocks anaphase, avoiding the segregation of damaged or incompletely replicated chromosomes. The checkpoint response has been proposed to constitute an anti-cancer barrier in human cells, preventing genomic instability in early tumorigenesis [3,4,5,6]
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