CDK Pho85 targets CDK inhibitor Sic1 to relieve yeast G1 checkpoint arrest after DNA damage.
In budding yeast, DNA damage in G1 activates a Rad9-dependent checkpoint that targets the cyclin-dependent kinase (CDK) Cdc28 to delay G1 exit. After a transient arrest, cells may enter S phase before completing DNA repair. We used genetic analysis to identify the stress-responsive CDK Pho85, the cyclin Pho80 and the targeted transcription factors Pho4 and Swi5 as determinants of G1 checkpoint adaptation. Consistent with opposing roles for the Cdc28 inhibitor Sic1 in blocking G1 exit and Pho85 in targeting Sic1 for proteolysis, mutation of Sic1 curtails G1 checkpoint delay, whereas Pho85 inhibition after DNA damage promotes Sic1 stability. G1 checkpoint delay in mutants lacking both Sic1 and Pho4 is independent of Pho85 activity. These data establish a G1 checkpoint adaptation pathway where Pho85 mediates Pho4 downregulation and Sic1 degradation to release Cdc28 activity and promote onset of S phase.
Wysocki
Robert
R
Institute of Genetics and Microbiology, Wroclaw University, 51-148 Wroclaw, Poland.
Javaheri
Ali
A
Kristjansdottir
Kolbrun
K
Sha
Fei
F
Kron
Stephen J
SJ
D017489:CDC28 Protein Kinase, S cerevisiae / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000502:physiology; D002478:Cells, Cultured; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000502:physiology; D015536:Down-Regulation; D005656:Fungal Proteins / Q000502:physiology; D016193:G1 Phase; D015966:Gene Expression Regulation, Fungal; D008954:Models, Biological; D020871:RNA Stability; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology
D018797:Cell Cycle Proteins; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; C060292:PHO4 protein, S cerevisiae; C086926:SIC1 protein, S cerevisiae; C080218:SWI5 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D017489:CDC28 Protein Kinase, S cerevisiae; D018844:Cyclin-Dependent Kinases; C058605:PHO85 protein, S cerevisiae