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A Suppressor Screen for the Characterization of Genetic Links Regulating Chronological Lifespan in Saccharomyces cerevisiae
Published on: September 17, 2020
HuR maintains a replicative life span by repressing the ARF tumor suppressor
Hiroyuki Kawagishi1, Michihiro Hashimoto, Hideaki Nakamura
1Research Institute, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan.
Molecular and Cellular Biology
|March 20, 2013
Summary
The RNA-binding protein HuR (human antigen R) represses p19(ARF) mRNA translation, maintaining cell lifespan. Loss of HuR causes premature senescence and impacts tissue function in aged animals.
Area of Science:
- Molecular biology
- Cellular senescence
- RNA regulation
Background:
- p19(ARF) is crucial for mouse cell senescence, with its expression regulated by methylation or deletion.
- While ARF expression is tightly controlled, its posttranscriptional regulation remains largely unexplored.
Purpose of the Study:
- To investigate the posttranscriptional regulation of p19(ARF) mRNA translation.
- To determine the role of HuR (human antigen R) in ARF mRNA translation and cellular senescence.
Main Methods:
- Utilized mouse embryonic fibroblasts (MEFs) to study ARF mRNA translation.
- Investigated the effects of HuR depletion on ARF mRNA levels, stability, and ribosome association.
- Examined ARF mRNA localization in nucleoli and its association with nucleolin.
- Generated adipose-specific HuR-deleted aged mice to assess in vivo effects.
Main Results:
- HuR represses p19(ARF) mRNA translation, maintaining the replicative lifespan of MEFs.
- Loss of HuR leads to premature senescence with increased p19(ARF) levels, but not p16(Ink4a).
- HuR depletion enhances ribosome association with ARF mRNA and promotes its accumulation in nucleoli.
- Adipose-specific HuR deletion in aged animals increases p19(ARF) expression and decreases insulin sensitivity.
Conclusions:
- p19(ARF) is regulated at the translational level by HuR.
- Translational control of p19(ARF) by HuR restrains cellular lifespan and tissue function in vivo.
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