PDF(Pubmed)
Abstract：
The relationship between aging and RNA biogenesis and trafficking is attracting growing interest, yet the precise mechanisms are unknown. The THO complex is crucial for mRNA cotranscriptional maturation and export. Herein, we report that the THO complex is closely linked to the regulation of lifespan. Deficiencies in Hpr1 and Tho2, components of the THO complex, reduced replicative lifespan (RLS) and are linked to a novel Sir2-independent RLS control pathway. Although transcript sequestration in hpr1Δ or tho2Δ mutants was countered by exosome component Rrp6, loss of this failed to mitigate RLS defects in hpr1Δ. However, RLS impairment in hpr1Δ or tho2Δ was counteracted by the additional expression of Nrd1-specific mutants that interacted with Rrp6. This effect relied on the interaction of Nrd1, a transcriptional regulator of aging-related genes, including ribosome biogenesis or RNA metabolism genes, with RNA polymerase II. Nrd1 overexpression reduced RLS in a Tho2-dependent pathway. Intriguingly, Tho2 deletion mirrored Nrd1 overexpression effects by inducing arbitrary Nrd1 chromatin binding. Furthermore, our genome-wide ChIP-seq analysis revealed an increase in the recruitment of Nrd1 to translation-associated genes, known to be related to aging, upon Tho2 loss. Taken together, these findings underscore the importance of Tho2-mediated Nrd1 escorting in the regulation of lifespan pathway through transcriptional regulation of aging-related genes.
摘要：
衰老与RNA生物发生和贩运之间的关系吸引了越来越多的兴趣，然而，确切的机制是未知的。THO复合物对于mRNA共转录成熟和输出至关重要。在这里，我们报告说，THO复合物与寿命的调节密切相关。THO复合物的组分Hpr1和Tho2的缺陷，减少复制寿命(RLS)，并与一种新的Sir2非依赖性RLS控制途径有关。尽管外泌体成分Rrp6抵消了hpr1Δ或tho2Δ突变体中的转录本隔离，但这种丢失未能减轻hpr1Δ中的RLS缺陷。然而,与Rrp6相互作用的Nrd1特异性突变体的额外表达抵消了hpr1Δ或tho2Δ中的RLS损伤。这种效应依赖于衰老相关基因的转录调节因子Nrd1的相互作用，包括核糖体生物发生或RNA代谢基因，RNA聚合酶II。Nrd1过表达降低Tho2依赖性途径中的RLS。有趣的是，Tho2缺失通过诱导任意Nrd1染色质结合反映了Nrd1过表达效应。此外，我们的全基因组ChIP-seq分析揭示了Nrd1对翻译相关基因的募集增加，已知与衰老有关，Tho2损失。一起来看,这些发现强调了Tho2介导的Nrd1护送在通过衰老相关基因的转录调节来调节寿命途径中的重要性.
