Cdc123 and checkpoint forkhead associated with RING proteins control the cell cycle by controlling eIF2gamma abundance.
Eukaryotic initiation factor 2 (eIF2) is a central regulator of translational initiation in times of growth and times of stress. Here we discovered three new conserved regulators of eIF2 in Saccharomyces cerevisiae. cdc123, homolog of mammalian D123, is a new cell division cycle mutant with a G2 delay at permissive temperature and a terminal, mating-proficient G1 arrest point. Cdc123 protein is regulated by nutrient availability. CHF1 and CHF2, homologs of mammalian checkpoint forkhead associated with RING genes, are required for G2 delay and G1 arrest of cdc123-4 and promote G1 delay when over-expressed. Cell cycle delaying activity and the natural instability of Chf1 and Chf2 depend on the integrity of both domains and association with Cdc123. Genetic analysis maps the Chf1 forkhead associated domain-binding site to the conserved Thr-274 of Cdc123, suggesting that mammalian D123 is a key target of Chfr. Gcd11, the gamma subunit of eIF2, is an additional Cdc123-interacting protein that is an essential target of the Cdc123 cell cycle promoting and Chf cell cycle arresting activity whose abundance is regulated by Cdc123, Chf1, and Chf2. Loss of cdc123 activity promotes Chf1 and Chf2 accumulation and Gcd11 depletion, accounting for the essentiality of Cdc123. The data establish the Cdc123-Chf-Gcd11 axis as an essential pathway for nutritional control of START that runs parallel to the Tor-Gcn2-Sui2 system of translational control.
Departments of Genetics and Biochemistry and the Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, New Hampshire 03756, USA.
Pawel
P
Bieganowski
Kara
K
Shilinski
Philip N
PN
Tsichlis
Charles
C
Brenner
D000483:Alleles; D000595:Amino Acid Sequence; D001483:Base Sequence; D001665:Binding Sites; D015153:Blotting, Western; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D015852:Eukaryotic Initiation Factor-2 / Q000096:biosynthesis* / Q000235:genetics*; D005434:Flow Cytometry; D016193:G1 Phase; D016195:G2 Phase; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006579:Heterozygote; D006801:Humans; D047468:Immunoprecipitation; D008954:Models, Biological; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D016366:Open Reading Frames; D010641:Phenotype; D010957:Plasmids / Q000378:metabolism; D014176:Protein Biosynthesis; D017434:Protein Structure, Tertiary; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D013696:Temperature; D013912:Threonine / Q000737:chemistry; D013997:Time Factors; D020798:Two-Hybrid System Techniques; D001616:beta-Galactosidase / Q000378:metabolism
C493791:Cdc123 protein, S cerevisiae; D018797:Cell Cycle Proteins; C493793:DMA2 protein, S cerevisiae; C493792:Dma1 protein, S cerevisiae; D015852:Eukaryotic Initiation Factor-2; D029701:Saccharomyces cerevisiae Proteins; D013912:Threonine; D001616:beta-Galactosidase