RESUMO
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RESUMO
The kinetochore is the crucial apparatus regulating chromosome segregation in mitosis and meiosis. Particularly in meiosis I, unlike in mitosis, sister kinetochores are captured by microtubules emanating from the same spindle pole (mono-orientation) and centromeric cohesion mediated by cohesin is protected in the following anaphase. Although meiotic kinetochore factors have been identified only in budding and fission yeasts, these molecules and their functions are thought to have diverged earlier. Therefore, a conserved mechanism for meiotic kinetochore regulation remains elusive. Here we have identified in mouse a meiosis-specific kinetochore factor that we termed MEIKIN, which functions in meiosis I but not in meiosis II or mitosis. MEIKIN plays a crucial role in both mono-orientation and centromeric cohesion protection, partly by stabilizing the localization of the cohesin protector shugoshin. These functions are mediated mainly by the activity of Polo-like kinase PLK1, which is enriched to kinetochores in a MEIKIN-dependent manner. Our integrative analysis indicates that the long-awaited key regulator of meiotic kinetochore function is Meikin, which is conserved from yeasts to humans.
Assuntos
Proteínas Cromossômicas não Histona/metabolismo , Sequência Conservada , Cinetocoros/metabolismo , Meiose , Animais , Proteínas de Ciclo Celular/metabolismo , Centrômero/metabolismo , Proteínas Cromossômicas não Histona/deficiência , Proteínas Cromossômicas não Histona/genética , Feminino , Humanos , Infertilidade/genética , Infertilidade/metabolismo , Masculino , Camundongos , Dados de Sequência Molecular , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteínas de Schizosaccharomyces pombe/metabolismo , Quinase 1 Polo-LikeRESUMO
In fission yeast, meiotic mono-orientation of sister kinetochores is established by cohesion at the core centromere, which is established by a meiotic cohesin complex and the kinetochore protein Moa1. The cohesin subunit Psm3 is acetylated by Eso1 and deacetylated by Clr6. We show that in meiosis, Eso1 is required for establishing core centromere cohesion during S phase, whereas Moa1 is required for maintaining this cohesion after S phase. The clr6-1 mutation suppresses the mono-orientation defect of moa1Δ cells, although the Clr6 target for this suppression is not Psm3. Thus, several acetylations are crucial for establishing and maintaining core centromere cohesion.
Assuntos
Meiose , Schizosaccharomyces/citologia , Schizosaccharomyces/metabolismo , Acetilação , Replicação do DNA , Prófase Meiótica I , Modelos Biológicos , Mutação/genética , Subunidades Proteicas/metabolismo , Proteínas de Schizosaccharomyces pombe/metabolismoRESUMO
The conserved kinetochore protein CENP-C plays a fundamental role in chromosome segregation, but its specific functions remain elusive. We have gained insights into the role of CENP-C through identification of interacting effector proteins required for kinetochore function in fission yeast. Fta1/CENP-L is a primary effector that associates directly with Cnp3/CENP-C, and ectopic localization of Fta1 largely suppresses the mitotic kinetochore defects of cnp3Delta cells. Pcs1 functions downstream of Cnp3 to prevent merotelic attachment. In meiosis, Cnp3 further associates with and recruits Moa1, a meiosis-specific protein exclusively required for the mono-orientation of kinetochores. Genetic and biochemical analyses identified Cnp3 mutants that preserve intact mitotic kinetochore function but abolish the association with Moa1 and meiotic mono-orientation. Overall, therefore, our studies identify effectors of CENP-C in mitosis and meiosis and establish the concept that CENP-C serves as a scaffold for the specific recruitment of essential kinetochore proteins.