MOLECULAR MECHANISMS OF LIFESPAN EXTENSION IN YEAST WITH IMPAIRED RIBOSOME RECYCLING

• Published in: Innovation in aging Vol. 2; no. suppl_1; p. 101
• Main Authors: Areshkov, P, Beaupere, C, Labunskyy, V
• Format: Journal Article
• Language: English
• Published: US Oxford University Press 11.11.2018
• Subjects: Abstracts
• ISSN: 2399-5300; 2399-5300
• DOI: 10.1093/geroni/igy023.379

Previous studies have identified hundreds of genes whose deletion extends replicative lifespan (RLS) of Saccharomyces cerevisiae. Among gene deletions that lead to RLS extension, a recent genome-wide analysis uncovered two genes, DOM34 and HBS1, encoding factors involved in recycling of terminating ribosomes (McCormick et al., 2015). However, the molecular mechanisms underlying increased longevity in the dom34Δ and hbs1Δ mutants are currently unknown. To investigate the role of these stalled ribosome rescue factors (Guydosh et al., 2014) in modulation of lifespan, we performed RNA-seq and ribosome profiling (Ribo-seq) analyses of S. cerevisiae strains lacking DOM34 and HBS1. Our results demonstrate that increased RLS in dom34Δ and hbs1Δ cells is associated with activated translation of genes involved in Fe transport and components of the mitochondrial electron transport chain, respectively. Moreover, both dom34Δ or hbs1Δ knockout strains were characterized by ~2 to 3-fold increase in ribosome footprints corresponding to ZTR1 mRNA, encoding a plasma membrane zinc transporter, and HAC1 transcription factor, a central regulator of the unfolded protein response (UPR) in yeast. However, further functional analysis did not reveal activation of the Hac1 transcription factor in the dom34Δ or hbs1Δ strains suggesting that increased HAC1 footprint coverage is likely caused by accumulation of stalled ribosomes on HAC1 truncated mRNA. Finally, we show that extended lifespan in cells lacking DOM34 and HBS1 is not due to a reduction in global mRNA translation. Implication of these findings for understanding molecular mechanisms that underlie RLS extension in the dom34Δ and hbs1Δ strains will be discussed.