Tho2-mediated escort of Nrd1 regulates gene expression for lifespan maintenance

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 maintaining a normal 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 hpr1? or tho2? mutants was countered by exosome component Rrp6, loss of this failed to mitigate RLS defects in hpr1?. However, RLS impairment in tho2? was counteracted by 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. Taken together, these findings underscore the importance of Tho2-mediated Nrd1 escorting in maintaining a normal lifespan by transcriptional regulation of aging-related genes. Overall design: Chromatin immunoprecipiation sequencing (ChIP-seq) for recruitment of Nrd1 by tho2?

衰老与RNA生物发生及RNA运输之间的关联正受到日益广泛的关注，但其确切的分子机制尚未明确。THO复合物（THO complex）对于mRNA的共转录成熟与输出过程至关重要。本研究发现，THO复合物与维持正常寿命密切相关。作为THO复合物的核心组分，Hpr1与Tho2的功能缺失会缩短细胞的复制寿命（replicative lifespan, RLS），且该现象与一条全新的不依赖Sir2的RLS调控通路相关。尽管hpr1Δ或tho2Δ突变体中出现的转录物滞留可通过外切体组分Rrp6得到缓解，但这一补救措施并未能改善hpr1Δ突变体的RLS缺陷。然而，tho2Δ突变体的RLS损伤可通过与Rrp6相互作用的Nrd1特异性突变体得以逆转。该保护效应依赖于Nrd1——一类调控衰老相关基因（包括核糖体生物发生或RNA代谢相关基因）转录的调控因子——与RNA聚合酶II的相互作用。Nrd1过表达会通过依赖Tho2的通路缩短细胞RLS。值得注意的是，THO2缺失会通过诱导非特异性的Nrd1染色质结合，模拟出Nrd1过表达所产生的效应。综上，上述研究结果凸显了Tho2介导的Nrd1靶向护送作用，通过对衰老相关基因进行转录调控，在维持正常寿命过程中的关键意义。整体实验设计：针对tho2Δ突变体中Nrd1招募情况的染色质免疫沉淀测序（Chromatin immunoprecipitation sequencing, ChIP-seq）