Studies on cell cycle regulatory mechanism which prevents production of aneuploid gametes due to chromosome mis-segregation during meiosis

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The anaphase-promoting complex/cyclosome (APC/C) promotes proteolysis of cell cycle regulators by ubiquitylating them. Cdh1 regulatory subunit activates APC/C from late anaphase to G1. Inactivation of Cdh1 (Ste9) in fission yeast causes inability of G1 arrest and sterility upon nutrient limitation. However, rneiosis restores in ste9 mutant when Ras-MAP kinase pathway is strongly activated by mating pheromone. In normal meiosis, homologous chromosomes segregate each other in first "reductional" division. In contrast, equational division occurs thus each sister chromosome segregates in first meiotic division in ste9 cells. As a result, chromosomes frequently mis-segregate in this mutant in meiosis. Similar defect is observed in cells lacking meiotic cohesin subunit Rec8, but GFP-Rec8 protein seems to localize in a chromatin region in ste9 cells undergoing meiosis, therefore inability of expression and localization of Rec8 is not a cause of aberrancy in this mutant. Previously, we reporte … More d that Ste9 is responsible for degradation of M phase cyclin (Cdc13), a representative substrate of APC/C, upon cell cycle arrest by nutrient deprivation. Protein levels of Cdc13 were monitored during meiosis by western blotting. In wild type strain; Cdc13 firstly disappeared during arrest in 01 phase, then re-appeared upon meiotic entry after premebtic DNA synthesis. In marked contrast, Cdc13 was kept at high levels throughout cell cycle arrest which mostly occurs in G2 phase, not in G1 in ste9 cells. In this mutant, DNA synthesis did not occur even after activation of Ras-MAP kinase pathway but surprisingly, meiotic nuclear division directly initiates from G2 phase. In this aberrant G2-exit meiosis, initial down-regulation of Cdc13 levels did not occur and meiosis directly started from high Cdc13 state. We concluded that by promoting Cdc13 degradation Ste9 plays an important role to prevent abortive meiosis from G2 phase and ensures initiation of meiosis from G1 that is necessary for proper chromosome segregation. Less