Identification of TRIML2, a Novel p53 Target, that Enhances p53 SUMOylation and Regulates the Transactivation of Proapoptotic Genes

Abstract

The tumor suppressor protein p53, encoded by TP53, inhibits tumorigenesis by inducing cell cycle arrest, senescence and apoptosis. Several genetic polymorphisms exist in TP53, including a proline to arginine variant at amino acid 72 (P72 and R72, respectively); this polymorphism alters p53 function. In general, the P72 variant shows increased ability to induce cell cycle arrest, while the R72 variant possesses increased ability to induce apoptosis, relative to P72. At present, the underlying mechanisms for these functional differences are not fully understood. Toward elucidating the molecular basis for these differences a gene expression microarray analysis was conducted on normal human fibroblast cells that are homozygous for P72 and R72 variants, along with subclones of these lines that express a p53 short hairpin (shp53). Approximately three dozen genes were identified whose transactivation is affected by the codon 72 polymorphism. One of these is the tripartite motif family-like 2 (TRIML2) gene, which is preferentially induced by the R72 variant. Importantly, the accumulated data indicate that TRIML2 interacts with p53, and facilitates the modification of p53 with SUMO2. TRIML2 also enhances the ability of p53 to transactivate a subset of pro-apoptotic target genes associated with prolonged oxidative stress, including PIDD, PIG3 (TP53I3) and PIG6 (PRODH). These data indicate that TRIML2 is part of a feed-forward loop that activates p53 in cells expressing the R72 variant, particularly after prolonged stress.

Subtelomeric p53 binding prevents accumulation of DNA damage at human telomeres

“…We found that cH2AX accumulated at higher levels at most subtelomeric positions tested in the 18q Dp53 relative to 18q WT CRISPR cell line ( Fig 7F and Appendix Fig S8). Additionally, we validated that human diploid fibrobasts depleted for p53 with shRNA (Kung et al, 2015) had similar changes in subtelomere regulation as did HCT116 cancer cell lines (Appendix Fig S9). We found that p53 depletion from human diploid fibroblasts increased global cH2AX in response to etoposide, along with the accumulation of cH2AX at subtelomeres, and reduced 18q subtelomeric transcription relative to normal diploid fibroblasts (Appendix Fig S9).…”

HMGA2 promotes intestinal tumorigenesis by facilitating MDM2‐mediated ubiquitination and degradation of p53

“…Post-translational modifications in p53 are critical processes that have effects on its stability [43][44][45][46]. In response to various genotoxic stresses, p53 is phosphorylated and acetylated at specific residues, thereby resulting in its stabilization and activation [43,47].…”

The role of the p53 tumor suppressor in metabolism and diabetes

“…This polymorphism can have significant impact on p53 function. In response to DNA damage, the P72 variant has been shown to promote a stronger cell cycle arrest phenotype, while the R72 variant is a superior inducer of apoptosis (Dumont, et al 2003; Kung, et al 2015), although tissue-specific differences to these phenotypes have been observed (Azzam, et al 2011). The impact of the codon 72 polymorphism on metabolic disease was not well studied, until recent reports linked this p53 SNP to susceptibility to diabetes.…”