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

초록

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 hpr1 Delta or tho2 Delta mutants was countered by exosome component Rrp6, loss of this failed to mitigate RLS defects in hpr1 Delta. However, RLS impairment in hpr1 Delta or tho2 Delta 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. Loss of Tho2 leads to an increase in Nrd1 recruitment to translation-associated genes, known as aging-related genes, thereby resulting in decreased expression of these genes. RLS impairment in tho2 Delta is counteracted by the disturbance of WT Nrd1 function due to the presence of Nrd1 mutants.image

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