Fission Yeast Ste9, a Homolog of Hct1/Cdh1 and Fizzy-related, Is a Novel Negative Regulator of Cell Cycle Progression during G₁-Phase

Abstract

When proliferating fission yeast cells are exposed to nitrogen starvation, they initiate conjugation and differentiate into ascospores. Cell cycle arrest in the G1-phase is one of the prerequisites for cell differentiation, because conjugation occurs only in the pre-Start G1-phase. The role ofste9 + in the cell cycle progression was investigated. Ste9 is a WD-repeat protein that is highly homologous to Hct1/Cdh1 and Fizzy-related. The ste9 mutants were sterile because they were defective in cell cycle arrest in the G1-phase upon starvation. Sterility was partially suppressed by the mutation in cig2 that encoded the major G1/S cyclin. Although cells lacking Ste9 function grow normally, the ste9 mutation was synthetically lethal with the wee1 mutation. In the double mutants ofste9 cdc10 ts, cells arrested in G1-phase at the restrictive temperature, but the level of mitotic cyclin (Cdc13) did not decrease. In these cells, abortive mitosis occurred from the pre-Start G1-phase. Overexpression of Ste9 decreased the Cdc13 protein level and the H1-histone kinase activity. In these cells, mitosis was inhibited and an extra round of DNA replication occurred. Ste9 regulates G1 progression possibly by controlling the amount of the mitotic cyclin in the G1-phase.

A Role for the START Gene–specific Transcription Factor Complex in the Inactivation of Cyclin B and Cut2 Destruction

“…However, we found that deletion of ste9/srw1 had little effect on the frequency of chromosomal abnormalities observed in mcs1-77 cells and by inference Cut2 stability. Because ubiquitination of Cut2 is not regulated by APC Ste9 but rather by a related complex, APC Slp1 , our results suggest that the MBF complex has an additional role in controlling APC activity (Funabiki et al, 1996;Matsumoto, 1997;Yamaguchi et al, 1997;Kitamura et al, 1998;Kominani et al, 1998). One obvious possibility is that the MBF complex may control the periodic transcription of one or more components or activators of the APC Slp1 complex.…”

“…Because APC-mediated degradation ceases after cells pass START, we suggest that repression of the MBF complex may play a key role in the inactivation of APC at this time. We considered that this may be due to either cell cycle-regulated production or modification of an APC subunit(s) or adaptor proteins such as Ste9/Srw1 (Yamaguchi et al, 1997;Kitamura et al, 1998;Kominani et al, 1998). In particular, we focused our attention on ste9/srw1, because it had been isolated previously as a multicopy suppressor of the mitotic catastrophe phenotype of ⌬mik1 wee1-50 cells at high temperature (Yamaguchi et al, 1997;H.…”

“…Ubiquitination and subsequent degradation of cyclin B is initiated by a specialized multisubunit ubiquitin ligase complex called the anaphase-promoting complex (APC) (reviewed by Page and Hieter, 1999;Zachariae and Nasmyth, 1999). The APC responsible for cyclin B degradation is found in association with an adaptor protein called Ste9/Srw1 (a homologue of CDH1/Fizzy-related) (Yamaguchi et al, 1997;Fang et al, 1998;Kitamura et al, 1998;Kominani et al, 1998). The APC is also responsible for the degradation of Cut2, an inhibitor of the metaphase-toanaphase transition, but in this case APC associates with a distinct adaptor protein called Slp1 (a homologue of CDC20/Fizzy) (Funabiki et al, 1996;Matsumoto, 1997).…”

Promoter-driven splicing regulation in fission yeast

“…Cdc13 degradation is directed by proteins from the APC complex, which recognize the Destruction Box (DB) present in some cyclins. Three known APC-complex proteins in S. pombe are Slp1, in mitosis, Ste9, in G1 and Mfr1/Fzr1 present during meiosis and sporulation (Asakawa et al, 2001;Blanco et al, 2001;Kitamura et al, 1998;Matsumoto, 1997;Yamada et al, 2000;Yamaguchi et al, 1997). Cdc13 main function is to promote the events of mitosis and avoid re-initiation of S phase (endoreduplication).…”

Modeling the fission yeast cell cycle: Quantized cycle times in wee1 − cdc25Δ mutant cells

“…At its core are antagonistic interactions between Cdc13͞Cdc2 (M-phase promoting factor, MPF) and its negative regulators, Ste9, Rum1, and Wee1͞Mik1. Ste9 targets Cdc13 subunits for ubiquitination by the APC (15,16). Rum1 is a cyclin-dependent kinase inhibitor, which reversibly binds to Cdc13͞Cdc2 and inhibits its activity (17).…”