Negative feedback regulation by HuR controls TRIM21 expression and function in response to UV radiation

Area of Science:

• Molecular Biology
• Cancer Research
• Immunology

Background:

• The E3 ubiquitin ligase TRIM21 regulates innate immunity and is implicated in genotoxic stress and tumor suppression.
• Previous studies indicated TRIM21 inhibits p53 synthesis by degrading HuR post-UV radiation, suggesting a pro-oncogenic function.
• TRIM21's role in DNA damage response and tumorigenesis requires further elucidation.

Purpose of the Study:

• To investigate the pro-oncogenic role of TRIM21 in response to DNA damage.
• To elucidate the regulatory feedback loop between TRIM21 and HuR.
• To explore the therapeutic potential of targeting the TRIM21-HuR interaction.

Main Methods:

• Cell proliferation assays (MCF7 cells) and colony formation assays.
• UV radiation treatment to induce DNA damage.
• Western blotting and RNA immunoprecipitation to assess protein and RNA levels.
• Dihydrotanshinone-I (DHTS-I) treatment to inhibit HuR-RNA binding.

Main Results:

• TRIM21 enhances MCF7 breast carcinoma cell proliferation and colony formation, counteracting UV-induced damage.
• TRIM21's pro-oncogenic effect is mediated by HuR degradation.
• HuR binds to TRIM21 mRNA's 3'UTR, activating its translation and forming a negative feedback loop.
• DHTS-I inhibits HuR-mediated TRIM21 upregulation while increasing p53 levels.

Conclusions:

• A negative feedback loop exists between TRIM21 and HuR, crucial for regulating p53 levels during genotoxic stress.
• TRIM21 exhibits a pro-oncogenic role in response to DNA damage via HuR degradation.
• Targeting the TRIM21-HuR interaction may offer therapeutic strategies for cancer treatment.