Folco H Diego, Chalamcharla Venkata R, Sugiyama Tomoyasu, Thillainadesan Gobi, Zofall Martin, Balachandran Vanivilasini, Dhakshnamoorthy Jothy, Mizuguchi Takeshi, Grewal Shiv I S
Laboratory of Biochemistry and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Nature. 2017 Mar 2;543(7643):126-130. doi: 10.1038/nature21372. Epub 2017 Feb 15.
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.
单亲二体性（UPD）是指个体含有一对仅来自一个亲本的同源染色体，这是一种常见现象，与先天性疾病和各种癌症有关。UPD被认为主要是由合子前或合子后染色体错分离导致的。然而，驱动UPD的因素仍然未知。在这里，我们使用裂殖酵母粟酒裂殖酵母作为模型来研究UPD，并表明RNA干扰（RNAi）机制或含YTH结构域的RNA消除因子Mmi1的缺陷会导致营养二倍体细胞中高水平的UPD。这种现象不是由于着丝粒处异染色质组装的缺陷。值得注意的是，在缺乏RNAi成分或Mmi1的细胞中，UPD与配子发生基因的过早表达有关。删除编码减数分裂黏连蛋白Rec8或细胞周期蛋白Crs1的上调基因可抑制RNAi和mmi1突变体中的UPD。此外，Rec8的过表达足以在野生型细胞中引发UPD。在营养细胞中表达的Rec8定位于染色体臂和着丝粒核心，在那里它是黏连蛋白亚基Psc3定位所必需的。Rec8和Psc3在着丝粒的定位通过独特地影响染色体分离促进UPD，导致一个同源物的减数分裂分离。总之，这些发现确定了配子发生基因的过早营养表达是UPD的一个致病因素，并为理解这一与多种人类疾病相关的现象提供了坚实的基础。
