A mutual inhibition between APC/C and its substrate Mes1 required for meiotic progression in fission yeast.
The anaphase-promoting complex/cyclosome (APC/C) is a cell-cycle-regulated essential E3 ubiquitin ligase; however, very little is known about its meiotic regulation. Here we show that fission yeast Mes1 is a substrate of the APC/C as well as an inhibitor, allowing autoregulation of the APC/C in meiosis. Both traits require a functional destruction box (D box) and KEN box. We show that Mes1 directly binds the WD40 domain of the Fizzy family of APC/C activators. Intriguingly, expression of nonubiquitylatable Mes1 blocks cells in metaphase I with high levels of APC/C substrates, suggesting that ubiquitylation of Mes1 is required for partial degradation of cyclin B in meiosis I by alleviating Mes1 inhibitory function. Consistently, a ternary complex, APC/C-Fizzy/Cdc20-Mes1, is stabilized by inhibiting Mes1 ubiquitylation. These results demonstrate that the fine-tuning of the APC/C activity, by a substrate that is also an inhibitor, is required for the precise coordination and transition through meiosis.
Kimata
Yuu
Y
Cell Cycle Control Laboratory, Marie Curie Research Institute, The Chart, Oxted, Surrey RH8 0TL, United Kingdom.
Trickey
Michelle
M
Izawa
Daisuke
D
Gannon
Julian
J
Yamamoto
Masayuki
M
Yamano
Hiroyuki
H
D064173:Anaphase-Promoting Complex-Cyclosome; D000818:Animals; D001665:Binding Sites; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005800:Genes, Fungal; D066298:In Vitro Techniques; D008540:Meiosis / Q000235:genetics / Q000502:physiology*; D008954:Models, Biological; D009865:Oocytes / Q000378:metabolism; D012568:Schizosaccharomyces / Q000166:cytology* / Q000235:genetics / Q000378:metabolism*; D029702:Schizosaccharomyces pombe Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity; D043743:Ubiquitin-Protein Ligase Complexes / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D014981:Xenopus
D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins; C432695:Mes1 protein, S pombe; D029702:Schizosaccharomyces pombe Proteins; C577504:slp1 protein, S pombe; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome