Tho2-mediated escort of Nrd1 regulates the expression of aging-related genes

Abstract

The relationship between aging and RNA biogenesis and trafficking is attracting grow-ing interest, yet the precise mechanisms are unknown. The THO complex is crucialfor mRNA cotranscriptional maturation and export. Herein, we report that the THOcomplex is closely linked to the regulation of lifespan. Deficiencies in Hpr1 and Tho2,components of the THO complex, reduced replicative lifespan (RLS) and are linkedto a novel Sir2-independent RLS control pathway. Although transcript sequestrationin hpr1Δ or tho2Δ mutants was countered by exosome component Rrp6, loss of thisfailed to mitigate RLS defects in hpr1Δ. However, RLS impairment in hpr1Δ or tho2Δwas counteracted by the additional expression of Nrd1-specific mutants that inter-acted with Rrp6. This effect relied on the interaction of Nrd1, a transcriptional regula-tor of aging-related genes, including ribosome biogenesis or RNA metabolism genes,with RNA polymerase II. Nrd1 overexpression reduced RLS in a Tho2-dependentpathway. Intriguingly, Tho2 deletion mirrored Nrd1 overexpression effects by induc-ing arbitrary Nrd1 chromatin binding. Furthermore, our genome-wide ChIP-seq analy-sis 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 under-score the importance of Tho2-mediated Nrd1 escorting in the regulation of lifespanpathway through transcriptional regulation of aging-related genes.