title: Untimely expression of gametogenic genes in vegetative cells causes uniparental disomy.
abstract: Uniparental disomy (UPD), in which an individual contains a pair of homologous chromosomes originating from only one parent, is a frequent phenomenon that is linked to congenital disorders and various cancers. UPD is thought to result mostly from pre- or post-zygotic chromosome missegregation. However, the factors that drive UPD remain unknown. Here we use the fission yeast Schizosaccharomyces pombe as a model to investigate UPD, and show that defects in the RNA interference (RNAi) machinery or in the YTH domain-containing RNA elimination factor Mmi1 cause high levels of UPD in vegetative diploid cells. This phenomenon is not due to defects in heterochromatin assembly at centromeres. Notably, in cells lacking RNAi components or Mmi1, UPD is associated with the untimely expression of gametogenic genes. Deletion of the upregulated gene encoding the meiotic cohesin Rec8 or the cyclin Crs1 suppresses UPD in both RNAi and mmi1 mutants. Moreover, overexpression of Rec8 is sufficient to trigger UPD in wild-type cells. Rec8 expressed in vegetative cells localizes to chromosomal arms and to the centromere core, where it is required for localization of the cohesin subunit Psc3. The centromeric localization of Rec8 and Psc3 promotes UPD by uniquely affecting chromosome segregation, causing a reductional segregation of one homologue. Together, these findings establish the untimely vegetative expression of gametogenic genes as a causative factor of UPD, and provide a solid foundation for understanding this phenomenon, which is linked to diverse human diseases.
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: H Diego
authors.initials: HD
authors.lastname: Folco
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Venkata R
authors.initials: VR
authors.lastname: Chalamcharla
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Tomoyasu
authors.initials: T
authors.lastname: Sugiyama
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Gobi
authors.initials: G
authors.lastname: Thillainadesan
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Zofall
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Vanivilasini
authors.initials: V
authors.lastname: Balachandran
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Jothy
authors.initials: J
authors.lastname: Dhakshnamoorthy
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Mizuguchi
authors.affiliation: Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Shiv I S
authors.initials: SI
authors.lastname: Grewal
mesh_terms: D002503:Centromere / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D020090:Chromosome Segregation / Q000235:genetics; D016213:Cyclins / Q000172:deficiency / Q000235:genetics; D004171:Diploidy; D015966:Gene Expression Regulation, Fungal; D005854:Germ Cells / Q000378:metabolism*; D006570:Heterochromatin / Q000378:metabolism; D006801:Humans; D008540:Meiosis / Q000235:genetics; D008954:Models, Biological; D009154:Mutation; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D012568:Schizosaccharomyces / Q000166:cytology* / Q000235:genetics*; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D024182:Uniparental Disomy / Q000235:genetics* / Q000473:pathology; D039221:mRNA Cleavage and Polyadenylation Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000097722:Cohesins
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D016213:Cyclins; D006570:Heterochromatin; D010750:Phosphoproteins; D029702:Schizosaccharomyces pombe Proteins; D039221:mRNA Cleavage and Polyadenylation Factors; C000621268:Crs1 protein, S pombe; C512176:Mmi1 protein, S pombe; C540906:psc3 protein, S pombe; D000097722:Cohesins; C077081:REC8 protein, S pombe