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Loss of RNA-binding protein HuR facilitates cellular senescence through posttranscriptional regulation of TIN2 mRNA.


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.

SUBMITTER: Lee JH 

PROVIDER: S-EPMC5934620 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Loss of RNA-binding protein HuR facilitates cellular senescence through posttranscriptional regulation of TIN2 mRNA.

Lee Ji Hoon JH   Jung Misun M   Hong Juyeong J   Kim Mi Kyung MK   Chung In Kwon IK  

Nucleic acids research 20180501 8


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 reg  ...[more]

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