ABSTRACT The exosome functions to regulate the cellular transcriptome through RNA biogenesis, surveillance, and decay. Mutations in Dis3, a catalytic subunit of the RNA exosome with separable endonuclease and exonuclease activities, are linked to multiple myeloma. Here we report that a cancer-associated DIS3 allele, dis3E729K, provides evidence for DIS3 functioning in mitotic fidelity in yeast. This dis3E729K allele does not induce defects in 7S→5.8S rRNA processing, although it elicits a requirement for P-body function. While it does not significantly influence cell cycle progression alone, the allele reduces the efficiency of cell cycle arrest in strains with defects in kinetochore assembly. Finally, point mutations in the exonuclease domains of yeast Dis3 elicit genome instability phenotypes; however, these DIS3 mutations do not increase DNA damage or RNA processing defects that lead to the accumulation of polyadenylated RNA in the nucleus. These data suggest that specific DIS3 activities support mitotic fidelity in yeast.

中文翻译：

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酵母 DIS3 的核酸外切酶域突变体表现出基因组不稳定性

摘要外泌体的功能是通过 RNA 生物发生、监视和衰变来调节细胞转录组。Dis3 是 RNA 外泌体的催化亚基，具有可分离的核酸内切酶和核酸外切酶活性，其突变与多发性骨髓瘤有关。在这里，我们报告了与癌症相关的 DIS3 等位基因 dis3E729K，为 DIS3 在酵母有丝分裂保真度中发挥作用提供了证据。该 dis3E729K 等位基因不会在 7S→5.8S rRNA 加工中引起缺陷，尽管它引发了对 P 体功能的要求。虽然它不会单独显着影响细胞周期进程，但等位基因会降低具有动粒组装缺陷的菌株中细胞周期停滞的效率。最后，酵母 Dis3 核酸外切酶域中的点突变引起基因组不稳定性表型；然而，这些 DIS3 突变不会增加导致聚腺苷酸化 RNA 在细胞核中积累的 DNA 损伤或 RNA 加工缺陷。这些数据表明特定的 DIS3 活动支持酵母中的有丝分裂保真度。