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

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 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.

ORGANISM(S): Saccharomyces cerevisiae

PROVIDER: GSE261087 | GEO | 2024/08/21

REPOSITORIES: GEO

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

Project description: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.

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Project description:RNAPII is responsible for transcription of protein-coding genes and short, regulatory RNAs. In Saccharomyces cerevisiae, termination of RNAPII-transcribed RNAs ≤1000 bases requires the NNS complex (comprised of Nrd1, Nab3, and Sen1) processing by the exosome, and the nuclear specific catalytic subunit, Rrp6. It has been shown that Rrp6 interacts directly with Nrd1, but whether or not Rrp6 is required for NNS-dependent termination is unclear. Loss of Rrp6 function may result in extension (or inhibition of termination) of NNS-dependent transcripts, or Rrp6 may only function after the fact to carry out RNA 3’ end processing. Here, we performed in-depth differential expression analyses and compare RNA-sequencing data of transcript length and abundance in cells lacking RRP6 to previously published sequencing data measuring the length of RNAs in Nrd1-depleted cells. We find many transcripts that were defined as unterminated upon loss of Nrd1 activity are of similar length in rrp6Δ, and expression levels of downstream genes are significantly decreased. This suggests a similar transcription interference mechanism occurs in cells lacking either Nrd1 or Rrp6, supporting the hypothesis that Rrp6 activity is required for proper NNS termination in vivo.

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Tho2 participates in yeast nuclear mRNP quality control by recruiting the 3'-5' exoribonuclease Rrp6

Project description:In order to dissect the nuclear RNA quality control (QC) mechanisms, we used a powerful assay based on global perturbation of mRNP biogenesis in yeast Saccharomyces cerevisiae by the bacterial Rho helicase. We have monitored the recruitment of THO complex subunit upon Rho activation, which revealed that Tho2 was over-recruited in opposition to its counterparts. We then tracked the recruitment of Rrp6 upon Rho induction in WT strain and in strains lacking either Mft1 or Tho2, showing the implication of Tho2 in Rrp6 recruitment over Rho induction. Finally, we measured the recruitment of Rrp6 upon partial deletion of Tho2 C-terminal domain responsible for its RNA interaction ability, proving that Tho2 presence on the chromatin is required for the Rho-induced Rrp6 recruitment..

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Characterization of extended transcripts by RNA-Seq suggests that Rrp6 influences Nrd1-dependent termination

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Protein chaperones elicit a caloric restriction-like response to extend replicative lifespan

Project description:The involvement of protein chaperones in aging is intriguing and their potential contribution has, so far, been attributed solely to their central role in proteostasis. Here we show that four protein chaperones from different cellular compartments extend replicative lifespan (RLS) in budding yeast by a common mechanism akin to caloric restriction. The RLS extension relies on the increased direct activation of Snf1 kinase by Hsp90, thereby bypassing the signal on the environmental glucose level. The chaperone-related RLS extension is accompanied by the uncoupling of the respiratory chain. A genomic approach confirmed the repression of glycolysis and cytoplasmic translation, and contrary, activation of gluconeogenesis and fatty acid oxidation. Our results set a novel paradigm for the role of protein chaperones: by modulation of the chaperone expression level one can affect metabolic features such as glucose sensing, fatty acid consumption, respiration rate, and, consequently, modify lifespan. We expect the described mechanism to open new avenues for research in aging and age-related diseases.

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

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

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

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

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Project description:Sgf73, a core component of the SAGA (Spt-Ada-Gcn5 Acetyltransferase) co-activator complex, is the yeast orthologue of ataxin-7, which in humans undergoes CAG ? polyglutamine repeat expansion to produce the neurodegenerative disease spinocerebellar ataxia type 7 (SCA7). We recently documented that deletion of SGF73 dramatically extends replicative lifespan (RLS) in yeast. To define the basis for Sgf73-mediated RLS extension, and to further explore the molecular function of Sgf73/ataxin-7 we performed ChIP-Seq for Sgf73 in yeast to identify its regions of DNA binding. The aim of the study was to uncover the underlying mechanisms controlled by Sgf73. This information will be used to understand the role of Sgf73 target genes in yeast aging pathways and possibly highlight pathways of mammalian aging regulation and SCA7 neurodegeneration in humans.

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Perturbation of mRNP biogenesis reveals a dynamic landscape of the Rrp6-dependent surveillance machinery trafficking along the yeast genome (RNA-seq dataset)

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Project description:In order to dissect the nuclear RNA quality control (QC) mechanisms, we used a powerful assay based on global perturbation of mRNP biogenesis in yeast Saccharomyces cerevisiae by the bacterial Rho helicase. We have monitored the global RNA levels upon Rho activation and compare it to basal RNA level in WT strain, which have revealed down-regulated transcripts. Then, the same experiment was performed but in a strain lacking Rrp47, giving us a precise overview of the QC targets (crosslinked dataset). We also followed some QC components (Nrd1, Nab3, Trf4 and Rrp6) along the yeast chromosomes by ChIP-seq before (NI) and after (I) perturbation of mRNP biogenesis by Rho.

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