The E3 ubiquitin ligase TRIM21 plays a crucial role as a negative regulator of innate immune responses. Recent evidence has also indicated the involvement of TRIM21 in the genotoxic stress response and suppressing tumorigenesis. Our previous work has demonstrated a new function of TRIM21 in inhibiting p53 protein synthesis by degrading the RNA-binding protein HuR in response to UV radiation. This suggested a pro-oncogenic role of TRIM21. In this study, we have shown that TRIM21 enhances the proliferation of MCF7 breast carcinoma cells and counteracts the decrease in cell proliferation and colony formation caused by UV-induced DNA damage. Further, this pro-oncogenic role of TRIM21 in response to DNA damage is mediated by its degradation of HuR. Conversely, we found that HuR binds to a U-rich element in the 3′UTR of TRIM21 mRNA and activates its translation, thereby constituting a negative feedback loop. We found that dihydrotanshinone-I (DHTS-I), a plantderived product which prevents HuR binding to specific RNAs, prevented HuR-mediated upregulation of TRIM21, while increasing the HuR-mediated upregulation of p53. Together, these findings demonstrate a negative feedback regulation between TRIM21 and HuR, which may play an important role in regulating the level of p53 in the genotoxic stress response. TRIM (Tripartite motif) family proteins are ubiquitously found in all metazoans and are recognized for conserved biological functions, such as control of cell proliferation and differentiation. However, with the appearance of complex immune systems in jawed vertebrates, some of these have evolved to directly regulate antiviral action and cytokine production. TRIM family proteins are primarily recognized as post-translational modifiers. Nevertheless, some of the members of this family are implicated in RNA metabolism. These TRIM proteins are specifically localized in the cytoplasmic processing bodies. Furthermore, about half of all the TRIM family proteins are involved in autophagy. Most of these are also involved in the formation of TRIMosomes which are considered to facilitate autophagic engulfment and subsequent lysosomal degradation 1. E3 ubiquitin ligase TRIM21 is a 52 kDa protein belonging to the TRIM family. Similar to many other TRIM family proteins, TRIM21 has a characteristic N-terminal RING domain, B-box domain, coiled-coil domain (collectively called RBCC). The RING domain is implicated in E3 ubiquitin ligase activity, whereas the B-box domain has been shown to be a negative regulator of RING domain. Recently, the phosphorylation of serine-80 (S80) or phosphomimetic serine-80 to glutamate (S80E) mutation in TRIM21 has been found to release the inhibition of B-box domain 2,3. The coiled-coil domain is utilized in homo-dimerization of TRIM21 which ensures binding with the substrate in a stoichiometry of 2:1 2. TRIM21 has also C-terminal PRYSPRY domain which is required for target protein recognition. Structural analysis of PRYSPRY domain of TRIM21 has demonstrated its diverse functions. Isothermal titration ca...