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J. Biol. Chem., Vol. 279, Issue 43, 44656-44666, October 22, 2004

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Cdc123 and Checkpoint Forkhead Associated with RING Proteins Control the Cell Cycle by Controlling eIF2 Abundance^*

Pawel Bieganowski, Kara Shilinski, Philip N. Tsichlis, and Charles Brenner¶

From the Departments of Genetics and Biochemistry and the Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, New Hampshire 03756 and Molecular Oncology Research Institute, Tufts-New England Medical Center, Boston, Massachusetts 02111

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 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.

Received for publication, June 2, 2004 , and in revised form, July 13, 2004.

^* This research was supported by NCI Research Grant CA77738 from the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) BK005577–BK005579.

^¶ To whom correspondence should be addressed. Tel.: 603-653-9922; Fax: 603-653-9923; E-mail: charles.brenner{at}dartmouth.edu.

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