Interplay between RNA-binding protein HuR and microRNA-125b regulates p53 mRNA translation in response to genotoxic stress.
Tumor suppressor protein p53 plays a crucial role in maintaining genomic integrity in response to DNA damage. Regulation of translation of p53 mRNA is a major mode of regulation of p53 expression under genotoxic stress. The AU/U-rich element-binding protein HuR has been shown to bind to p53 mRNA 3'UTR and enhance translation in response to DNA-damaging UVC radiation. On the other hand, the microRNA miR-125b is reported to repress p53 expression and stress-induced apoptosis. Here, we show that UVC radiation causes an increase in miR-125b level in a biphasic manner, as well as nuclear cytoplasmic translocation of HuR. Binding of HuR to the p53 mRNA 3'UTR, especially at a site adjacent to the miR-125b target site, causes dissociation of the p53 mRNA from the RNA-induced silencing complex (RISC) and inhibits the miR-125b-mediated translation repression of p53. HuR prevents the oncogenic effect of miR-125b by reversing the decrease in apoptosis and increase in cell proliferation caused by the overexpression of miR-125b. The antagonistic interplay between miR-125b and HuR might play an important role in fine-tuning p53 gene expression at the post-transcriptional level, and thereby regulate the cellular response to genotoxic stress.
a Department of Biological Sciences , Indian Institute of Science Education and Research , Kolkata, Mohanpur, Nadia , West Bengal , India.
Deepika
D
Ahuja
a Department of Biological Sciences , Indian Institute of Science Education and Research , Kolkata, Mohanpur, Nadia , West Bengal , India.
Ashish
A
Goyal
a Department of Biological Sciences , Indian Institute of Science Education and Research , Kolkata, Mohanpur, Nadia , West Bengal , India.
Partho Sarothi
PS
Ray
D020413:3' Untranslated Regions; D017209:Apoptosis; D004249:DNA Damage; D000067780:ELAV-Like Protein 1 / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000528:radiation effects; D006801:Humans; D061986:MCF-7 Cells; D035683:MicroRNAs / Q000235:genetics*; D014176:Protein Biosynthesis; D021381:Protein Transport / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D020413:3' Untranslated Regions; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; C531888:MIRN125 microRNA, human; D035683:MicroRNAs; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
Cancer; DNA damage; HuR; RNA-binding protein; miR-125b; microRNA; p53; translation regulation