Mutations of EXOSC3/Rrp40p associated with neurological diseases impact ribosomal RNA processing functions of the exosome in S. cerevisiae.
Mutations of EXOSC3/Rrp40p associated with neurological diseases impact ribosomal RNA processing functions of the exosome in S. cerevisiae.
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DOI：
10.1261/rna.060004.116
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发表时间：
2017-04
期刊：
影响因子：
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通讯作者：
Chanfreau GF
中科院分区：
文献类型：
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作者：
Gillespie A;Gabunilas J;Jen JC;Chanfreau GF
RNA外泌体是一种保守的多蛋白复合物，在真核细胞中实现大量的加工和降解功能。最近，突变已被映射到编码外泌体的亚基之一EXOSC 3（酵母Rrp 40 p）的基因，其导致人类患者的脑桥小脑发育不全伴运动神经元变性。然而，这些突变在这些疾病的病理学中的分子影响尚不清楚。为了研究导致神经系统疾病的EXOSC 3突变的分子后果，我们分析了影响S中EXOSC 3/Rrp 40 p保守残基的三种突变（G31 A，G191 C和W238 R; G8 A，G148 C和W195 R，分别在人类和酵母中）的影响。啤酒。我们发现，这些突变在酵母中的表型的严重程度与人类患者的疾病相关，W195 R突变体显示出最强的生长和RNA加工表型。此外，我们发现这些突变更严重地影响外泌体的前核糖体RNA加工功能，而不是其他核加工或监视功能。这些结果表明，延迟或有缺陷的前rRNA加工可能是导致在具有影响EXOSC 3功能的突变的患者中检测到的病理的主要缺陷，该突变在整个真核生物中保守的残基中。
The RNA exosome is a conserved multiprotein complex that achieves a large number of processive and degradative functions in eukaryotic cells. Recently, mutations have been mapped to the gene encoding one of the subunits of the exosome, EXOSC3 (yeast Rrp40p), which results in pontocerebellar hypoplasia with motor neuron degeneration in human patients. However, the molecular impact of these mutations in the pathology of these diseases is not well understood. To investigate the molecular consequences of mutations in EXOSC3 that lead to neurological diseases, we analyzed the effect of three of the mutations that affect conserved residues of EXOSC3/Rrp40p (G31A, G191C, and W238R; G8A, G148C, and W195R, respectively, in human and yeast) in S. cerevisiae. We show that the severity of the phenotypes of these mutations in yeast correlate with that of the disease in human patients, with the W195R mutant showing the strongest growth and RNA processing phenotypes. Furthermore, we show that these mutations affect more severely pre-ribosomal RNA processing functions of the exosome rather than other nuclear processing or surveillance functions. These results suggest that delayed or defective pre-rRNA processing might be the primary defect responsible for the pathologies detected in patients with mutations affecting EXOSC3 function in residues conserved throughout eukaryotes.