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 hpr1Δ or tho2Δ mutants was countered by exosome component Rrp6, loss of this failed to mitigate RLS defects in hpr1Δ. However, RLS impairment in tho2Δ 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. Chromatin immunoprecipiation sequencing (ChIP-seq) for recruitment of Nrd1 by tho2Δ

衰老与RNA生物发生及转运之间的关联正受到越来越多的关注，但其确切机制尚不清楚。THO复合物（THO complex）对于mRNA的共转录成熟与输出至关重要。本文报道称，THO复合物与正常寿命的维持密切相关。THO复合物的组分Hpr1与Tho2的缺失会缩短复制寿命（replicative lifespan, RLS），并与一条新的不依赖Sir2的RLS调控通路相关。尽管hpr1Δ或tho2Δ突变体中的转录本滞留可通过外切体组分Rrp6得以缓解，但该蛋白的缺失并未能改善hpr1Δ突变体的RLS缺陷。然而，tho2Δ突变体中的RLS损伤可通过与Rrp6相互作用的Nrd1特异性突变体得到逆转。这一效应依赖于Nrd1——一类衰老相关基因（包括核糖体生物发生或RNA代谢基因）的转录调控因子——与RNA聚合酶II（RNA polymerase II）的相互作用。Nrd1的过表达会通过依赖Tho2的通路缩短RLS。有趣的是，THO2的缺失通过诱导无特异性的Nrd1染色质结合，模拟了Nrd1过表达的效应。综上，上述研究结果强调了Tho2介导的Nrd1伴护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重要性。针对tho2Δ突变体中Nrd1招募情况的染色质免疫沉淀测序（ChIP-seq）