The meiotic cell cycle is modified from the mitotic cell cycle by having a premeiotic S phase which leads to high levels of recombination, two rounds of nuclear division with no intervening DNA synthesis, and a reductional pattern of chromosome segregation. Rem1 is a cyclin that is expressed only during meiosis in the fission yeast Schizosaccharomyces pombe. Cells in which rem1 has been deleted show a decreased intragenic meiotic recombination and a delay at the onset of meiosis I. When ectopically expressed in mitotically growing cells, Rem1 induces a G1 arrest followed by severe mitotic catastrophes. Here we show that rem1 expression is regulated at the level of both transcription and splicing, encoding for two proteins with different function depending on the intron retention. We have determined that the regulation of rem1 splicing is not dependent on any transcribed region of the gene. Furthermore, when the rem1 promoter is fused to other intron-containing genes, the chimeras show a meiotic-specific regulation of splicing, exactly as endogenous rem1. This regulation is dependent on two transcription factors of the forkhead family, Mei4 and Fkh2. While Mei4 induces both transcription and splicing of rem1, Fkh2 is responsible for the intron retention of the transcript during vegetative growth and pre-meiotic S phase. / El ciclo meiótico se diferencia del ciclo mitótico por tener una fase S pre-meiótica caracterizada por altos niveles de recombinación, dos rondas de división nuclear sin síntesis de DNA entre las dos y una segregación cromosómica reduccional. Rem1 es una ciclina que sólo se expresa en meiosis en la levadura de fisión Schizosaccharomyces pombe. Celulas con rem1 deleccionado presentan una tasa de recombinación intragénica disminuida y un retraso en el inicio de meiosis I. Cuando se expresa ectópicamente en células creciendo vegetativamente, Rem1 induce un arresto en G1 seguido de catástrofe mitótica. Este trabajo describe que la expresión de rem1 está regulada a nivel de la trascripción y el procesamiento, codificando para dos proteínas con funciones diferentes dependiendo de la retención intrónica.. Hemos determinado que la regulación del splicing de rem1 no depende de ninguna región transcrita del gen. Además, cuando el promotor se fusiona a otros genes que contienen intrones, las quimeras presentan una regulación específica de meiosis como el rem1 endógeno. Esta regulación depende de dos factores de transcripción de la familia Forkhead, Mei4 y Fkh2. Mientras Mei4 induce la transcripción y el splicing de rem1, Fkh2 es responsable de la retención intrónica del tránscrito durante crecimiento vegetativo y fase S pre-meiótica.

Forkhead box (Fox) transcription factors have a conserved function in regulating lifespan and onset of age related disease in organisms from worms to mammals. Key functions in this process are the regulation of the cell cycle, oxidative stress response, and apoptosis. A complex post-translational code from nutrient, growth factor, and stress induced signals regulates Fox activity, target specificity, stability, and subcellular localization; however, many of the Fox mechanisms and targets responsible for regulating lifespan remain elusive. The budding yeast, Saccharomyces cerevisiae, is a powerful model for unravelling the genetic mechanism and pathways. Yeast encodes four Fox transcription factors, Fkh1, Fkh2, Fhl1 and Hcm1, and their roles in aging are only recently being examined. In this study, we utilized the chronological lifespan and oxidative stress assays, to explore evolutionary conservation of lifespan regulation in two of the yeast Fox orthologs, FKH1 and FKH2. We observed that deletion of both FKH genes in S. cerevisiae, impedes normal lifespan and stress resistance. Furthermore, fkh1Δ fkh2Δ cells were found to be non-responsive to caloric restriction, an intervention that extends lifespan from yeast to mammals. Conversely, increased expression of the FKHs leads to extended lifespan and improved stress resistance. Additionally, we show the Anaphase-Promoting Complex (APC) genetically interacts with the FKHs, likely functioning in a linear pathway under normal conditions, as fkh1Δ fkh2Δ post-mitotic survival defect is epistatic to that observed in apc5CA mutants. However, under stress conditions, post-mitotic survival is dramatically impaired in apc5CA fkh1Δ fkh2Δ beyond either apc5CA or fkh1Δ fkh2Δ. Finally, we observed that both the FKHs and APC genetically interact with nutrient-responsive lifespan-regulating kinase encoding genes SCH9 and TOR1. This study establishes that the yeast FKHs play a role as regulators of lifespan in yeast and identifies the APC as a novel component of this mechanism. We speculate this involves combined regulation of stress response, genomic stability, and cell cycle.