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PMID: 10444592 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Pds1 and Esp1 control both anaphase and mitotic exit in normal cells and after DNA damage.

Genes & development ·Vol. 13 ·No. 15 ·1999-08-01 ·Pages 1936-49

Tinker-Kulberg RL, Morgan DO

Abstract

The separation of sister chromatids in anaphase is followed by spindle disassembly and cytokinesis. These events are governed by the anaphase-promoting complex (APC), which triggers the ubiquitin-dependent proteolysis of key regulatory proteins: anaphase requires the destruction of the anaphase inhibitor Pds1, whereas mitotic exit requires the destruction of mitotic cyclins and the inactivation of Cdk1. We find that Pds1 is not only an inhibitor of anaphase, but also blocks cyclin destruction and mitotic exit by a mechanism independent of its effects on sister chromatid separation. Pds1 is also required for the mitotic arrest and inhibition of cyclin destruction that occurs after DNA damage. Even in anaphase cells, where Pds1 levels are normally low, DNA damage stabilizes Pds1 and prevents cyclin destruction and mitotic exit. Pds1 blocks cyclin destruction by inhibiting its binding partner Esp1. Mutations in ESP1 delay cyclin destruction; overexpression of ESP1 causes premature cyclin destruction in cells arrested in metaphase by spindle defects and in cells arrested in metaphase and anaphase by DNA damage. The effects of Esp1 are dependent on Cdc20 (an activating subunit of the APC) and on several additional proteins (Cdc5, Cdc14, Cdc15, Tem1) that form a regulatory network governing mitotic exit. We speculate that the inhibition of cyclin destruction by Pds1 may contribute to the ordering of late mitotic events by ensuring that mitotic exit is delayed until after anaphase is initiated. In addition, the stabilization of Pds1 after DNA damage provides a mechanism to delay both anaphase and mitotic exit while DNA repair occurs.

MeSH Terms
Anaphase CDC2 Protein Kinase/metabolism Cdh1 Proteins Cell Cycle Proteins/genetics,metabolism Chromosome Segregation Cyclin B/metabolism Cyclin-Dependent Kinase Inhibitor Proteins Cyclins/metabolism DNA Damage/genetics DNA-Binding Proteins/genetics,metabolism Fungal Proteins/genetics,metabolism G1 Phase Gene Expression Genes, Fungal/genetics,physiology Metaphase Mitosis Mutation Nuclear Proteins/genetics,metabolism Proteins Proto-Oncogene Proteins c-myc/antagonists & inhibitors,genetics,metabolism Rad52 DNA Repair and Recombination Protein Saccharomyces cerevisiae/cytology,genetics,metabolism Saccharomyces cerevisiae Proteins Securin
Chemicals
CLB2 protein, S cerevisiae Cdh1 Proteins Cell Cycle Proteins Cyclin B Cyclin-Dependent Kinase Inhibitor Proteins Cyclins DNA-Binding Proteins Fungal Proteins Nuclear Proteins PDS1 protein, S cerevisiae Proteins Proto-Oncogene Proteins c-myc RAD52 protein, S cerevisiae Rad52 DNA Repair and Recombination Protein SIC1 protein, S cerevisiae Saccharomyces cerevisiae Proteins Securin cysteine-rich protein, mammalian rad9 protein CDC2 Protein Kinase
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Tinker-Kulberg R L
Department of Physiology, University of California, San Francisco, California 94143-0444, USA.
Morgan D O
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Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
0890-9369
DOI
10.1101/gad.13.15.1936
Published
1999-08-01
Pages
1936-49
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC316917
Subset
IM
External Links
PubMed source DOI: 10.1101/gad.13.15.1936 PMC Full Text View journal details
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