Investigating the Role and Regulation of RNA-binding Protein HuR and microRNA miR-125b in Regulating p53 mRNA Translation Post Genotoxic Stress

Ahuja, Deepika (2018) Investigating the Role and Regulation of RNA-binding Protein HuR and microRNA miR-125b in Regulating p53 mRNA Translation Post Genotoxic Stress. PhD thesis, Indian Institute of Science Education and Research Kolkata.

PDF (PhD thesis of Deepika Ahuja (10RS020)) 10RS020.pdf - Submitted Version Restricted to Repository staff only Download (5MB)

Abstract

In this thesis, we have elucidated the role of RNA-binding protein HuR and microRNA miR-125b in regulating p53 mRNA translation in response to genotoxic stress. We have further provided insights into the regulation of miR-125b and HuR, which determines p53 expression in response to DNA damage. UVC irradiation causes the nuclear-cytoplasmic shuttling of HuR, leading to enhanced binding of HuR to p53 mRNA 3‘UTR, thereby causing the dissociation of p53 mRNA bound miR-125b-RISC complex and prevents miR-125b mediated translation repression. HuR also counteracts the cell proliferation and anti-apoptotic activity of miR-125b. We have also shown a very interesting dual role of HuR and miR-125b, dependent on p53, in regulating cell proliferation and apoptosis. By a combination of dynamic systems modeling and experimental validation, we have discovered TRIM21, an E3 ubiquitin ligase, and miR-125b as two novel regulators of HuR in the p53 regulatory network which contributes to the pulsatile expression of p53 post DNA damage. Finally, we have also shown p53 as a transcriptional regulator of miR-125b gene, causing, in part, the enhancement of miR-125b expression in response to DNA damage. Briefly, this thesis integrates the regulation of translation, transcription and protein degradation that culminates into a coordinated response of p53 expression in response to genotoxic stress.

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