Cdc53p Acts in Concert with Cdc4p and Cdc34p To Control the G₁-to-S-Phase Transition and Identifies a Conserved Family of Proteins

Abstract

Regulation of cell cycle progression occurs in part through the targeted degradation of both activating and inhibitory subunits of the cyclin-dependent kinases. During G 1 , CDC4, encoding a WD-40 repeat protein, and CDC34, encoding a ubiquitin-conjugating enzyme, are involved in the destruction of these regulators. Here we describe evidence indicating that CDC53 also is involved in this process. Mutations in CDC53 cause a phenotype indistinguishable from those of cdc4 and cdc34 mutations, numerous genetic interactions are seen between these genes, and the encoded proteins are found physically associated in vivo. Cdc53p defines a large family of proteins found in yeasts, nematodes, and humans whose molecular functions are uncharacterized. These results suggest a role for this family of proteins in regulating cell cycle proliferation through protein degradation.

Two F‐box/WD‐repeat proteins Pop1 and Pop2 form hetero‐ and homo‐complexes together with cullin‐1 in the fission yeast SCF (Skp1‐Cullin‐1‐F‐box) ubiquitin ligase

“…Budding yeast contains, in addition to Cdc53, two ORFs which are cullin members. However, these two proteins are not particularly similar to either cullin-3 or cullin-4 (< 25% identity, Mathias et al 1996). Fission yeast therefore contains multiple cullin homologues which are evolutionarily more conserved towards human homologues rather than towards budding yeast.…”

“…Identical amino acid residues are marked (shadowed boxes with black letters), in particular, residues in which all the four cullin homologues contain identical amino acid are emphasized with closed boxes with white letters. It was incorrectly reported previously that Pcu3 is a cullin-1 homologue of fission yeast (Mathias et al 1996). (B) Evolutional phylogeny among members of a cullin family from different organisms is shown.…”

Novelsfi1Alleles Uncover Additional Functions for Sfi1p in Bipolar Spindle Assembly and Function

“…Another mutant that arrests at a similar stage is cdc4, an F-box component of the ubiquitin ligase known as the SCF (Mathias et al, 1996;Cardozo and Pagano, 2004). This suggests the possibility that an SCF substrate needs to be degraded, by ubiquitin-mediated proteolysis, for bridge separation to occur.…”

A Role for Saccharomyces cerevisiae Cul8 Ubiquitin Ligase in Proper Anaphase Progression

“…The Cdc53 component of the yeast SCF E3 ligase belongs to an evolutionarily conserved family of proteins known as cullins that contains three related genes in both budding and fission yeast and at least six genes in worm, fruit fly, and human (6,7). The functional importance and conservation of cullins is underscored by the finding that a subunit of APC E3 ligase, APC2, contains limited sequence homology to cullins (8,9).…”

“…Ample genetic evidence establishes that cullin proteins perform various physiological functions critical not only to the cell cycle but also to cell growth and animal development. Mutations in CDC53 caused a G 1 cell cycle arrest in both budding and fission yeast (7,10), but abrogation of its orthologue, CUL1, did not inhibit somatic cell cycle progression in higher eukaryotes. Instead, mutations in Caenorhabditis elegans cul-1 caused hyperplasia of blast-cell lineages (6), and mutations in mouse CUL1 and CUL3 resulted in early embryonic lethality with a correlative accumulation of G 1 cyclin E (11)(12)(13).…”