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Abstract
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.
Highlights
Eukaryotic cell division cycles consist of a number of dependent and independent gene-controlled sequences that are coordinated by gene-controlled checkpoints that ensure fidelity [1]
Interaction of Cdc123 with Checkpoint Forkhead Associated with RING Proteins Mediates FHA Domain and RING Domaindependent Destabilization of the Chf Proteins—To identify additional components of the cell cycle machinery controlled by Cdc123, we performed a two-hybrid screen and identified both yeast homologs of human checkpoint forkhead associated with RING protein, Chfr
We identify CDC123 as the yeast homolog of mammalian D123, and we characterize its functions in cell cycle progression as a molecule positively regulated by nutrients, as a negative regulator of yeast homologs of Chfr, and as a regulator of Eukaryotic initiation factor 2 (eIF2)␥ abundance
Summary
Eukaryotic cell division cycles consist of a number of dependent and independent gene-controlled sequences that are coordinated by gene-controlled checkpoints that ensure fidelity [1]. Plasmid pB295 carrying the CDC123 gene under GAL1 promoter control was created by cloning the PCR product generated with primers 7832 and 7833 between BamHI and XhoI sites of plasmid p425GAL1.
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