HuR stabilizes TFAM mRNA in an ATM/p38-dependent manner in ionizing irradiated cancer cells.

Mitochondrial transcription factor A (TFAM) plays key roles in transcription and maintenance of mtDNA. It has been reported that TFAM could promote the proliferation and tumorigenesis of cells under stressed conditions. Previous evidence showed ionizing radiation stimulated the expression of TFAM, the replication of mtDNA, and the activity of mtDNA-encoded cytochrome C oxidase. However, little is known about the mechanism of TFAM regulation in irradiated cells. In this article, we explored the role of mRNA stability in regulating TFAM expression in irradiated cancer cells. Our results showed that radiation stimulated the levels of TFAM mRNA and protein. RNA-binding protein HuR associated and stabilized TFAM mRNA to facilitate the expression of TFAM, which was enhanced by radiation. Furthermore, radiation-activated ataxia-telangiectasia mutated kinase/p38 signaling positively contributed to the nucleus to cytosol translocation of HuR, its binding and stabilization of TFAM mRNA, without affecting the transcription and the stability of TFAM. Our current work proposed a new mechanism of DNA damage response-regulated mitochondrial function variations, and indicated that TFAM might be a potential target for increasing the sensitization of cancer cells to radiotherapy.