Abstract
Cellular senescence can be induced by high levels of reactive oxygen species (ROS) produced by mitochondria. However, the mechanism by which elevated mitochondrial ROS levels are produced during replicative senescence is not yet fully understood. Here, we report that loss of the RNA-binding protein, human antigen R (HuR), during replicative senescence leads to an increase in ROS levels through enhanced mitochondrial localization of the telomeric protein TIN2. HuR binds to the 3 untranslated region of TIN2 mRNA. This association decreases TIN2 protein levels by both destabilizing TIN2 mRNA and reducing its translation. Conversely, depletion of HuR levels enhances TIN2 expression, leading to increased mitochondrial targeting of TIN2. Mitochondrial localization of TIN2 increases ROS levels, which contributes to induction and maintenance of cellular senescence. Our findings provide compelling evidence for a novel role of HuR in controlling the process of cellular senescence by regulating TIN2-mediated mitochondrial ROS production, and for a useful therapeutic route for modulating intracellular ROS levels in treating both aging-related complications and cancer.
Original language | English |
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Pages (from-to) | 4271-4285 |
Number of pages | 15 |
Journal | Nucleic acids research |
Volume | 46 |
Issue number | 8 |
DOIs | |
Publication status | Published - 2018 May 4 |
Bibliographical note
Funding Information:National Research Foundation of Korea [NRF-2013M3A9B6076431, NRF-2016R1A5A1010764 to I.K.C.]; Yonsei University Intramural Research [2014-22-0096 to I.K.C.]. Funding for open access charge: National Research Foundation of Korea.
Funding Information:
National Research Foundation of Korea [NRF-2013M3A9B6076431, NRF-2016R1A5A1010764 to I.K.C.]; Yonsei University Intramural Research [2014-22-0096 to I.K.C.]. Funding for open access charge: National Research Foundation of Korea. Conflict of interest statement. None declared.
Publisher Copyright:
© The Author(s) 2018. Published by Oxford University Press on behalf of Nucleic Acids Research.
All Science Journal Classification (ASJC) codes
- Genetics