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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
p53 and HuR combinatorially control the biphasic dynamics of microRNA-125b in response to genotoxic stress
Binita Goswami1, Deepika Ahuja1, David Pastré2
1Department of Biological Sciences, Indian Institute of Science Education and Research, Kolkata, Mohanpur, Nadia, 741246, West Bengal, India.
Abstract:
Post-transcriptional regulation of p53, by the microRNA miR-125b and the RNA-binding protein HuR, controls p53 expression under genotoxic stress. p53 mRNA translation is repressed by miR-125b, tightly regulating its basal level of expression. The repression is relieved upon DNA damage by a decrease in miR-125b level, contributing to pulsatile expression of p53. The pulse of p53, as also of HuR, in response to UV irradiation coincides with a time-dependent biphasic change in miR-125b level. We show that the cause for the decrease in miR-125b level immediately post DNA-damage is enhanced exosomal export mediated by HuR. The subsequent increase in miR-125b level is due to p53-mediated transcriptional upregulation and enhanced processing, demonstrating miR-125b as a transcriptional and processing target of p53. p53 activates the transcription of primary miR-125b RNA from a cryptic promoter in response to UV irradiation. Together, these regulatory processes constitute reciprocal feedback loops that determine the biphasic change in miR-125b level, ultimately contributing to the fine-tuned temporal regulation of p53 expression in response to genotoxic stress.
Insights
MicroRNA miR-125b and HuR protein regulate p53 expression during genotoxic stress. HuR enhances miR-125b export post-damage, while p53 upregulates miR-125b, creating feedback loops for precise p53 temporal control.
Area of Science:
- Molecular Biology
- Cellular Stress Response
- Gene Regulation
Background:
- p53 is a critical tumor suppressor involved in cellular stress response.
- MicroRNAs (miRNAs) and RNA-binding proteins (RBPs) are key post-transcriptional regulators.
- Dysregulation of p53 contributes to cancer development.
Purpose of the Study:
- To elucidate the roles of miR-125b and HuR in p53 regulation under genotoxic stress.
- To investigate the mechanisms controlling miR-125b levels following DNA damage.
- To understand the feedback loops governing p53 expression dynamics.
Main Methods:
- Analysis of p53 mRNA translation and miR-125b levels.
- Investigating HuR-mediated exosomal export of miR-125b.
- Assessing p53-dependent transcriptional upregulation and processing of miR-125b.
- Utilizing UV irradiation as a genotoxic stress inducer.
Main Results:
- miR-125b represses basal p53 expression; its level decreases post-DNA damage, relieving repression.
- HuR mediates enhanced exosomal export of miR-125b immediately after DNA damage.
- p53 induces transcriptional upregulation and enhanced processing of miR-125b, creating a feedback loop.
- Reciprocal feedback between p53 and miR-125b results in biphasic changes in miR-125b levels.
Conclusions:
- miR-125b and HuR are crucial for the post-transcriptional control of p53 under genotoxic stress.
- HuR-mediated exosomal export and p53-driven transcriptional regulation establish feedback loops controlling miR-125b dynamics.
- These regulatory mechanisms ensure fine-tuned, pulsatile p53 expression in response to DNA damage.
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