Absent the carboxy terminus of the full-length p53 protein, p53-R9 lacks the residues necessary for canonical p53 tetramerization and predicted full DNA-binding potential. This gene encodes for p53-R9 protein, which has 180 amino acids and 54.1% pairwise identity when aligned to the full-length elephant p53 protein (Fig. Of the ~20 TP53 retrogenes in the African elephant genome, TP53-RETROGENE 9 ( TP53-R9) (GenBank KF715863, Ensembl ENSLAFG00000028299) was reported to be the most highly expressed in various Asian and African elephant tissues. Discovering the mechanisms of these evolved defenses may inform the development of therapeutics to treat or prevent human cancers. Increased TP53 copy number and enhanced TP53 activity may be part of the elephant’s solution to Peto’s paradox, protecting them from increased oncogenic risk due to their body size and lifespan. A recent study of cancer prevalence in elephants under human care found no malignant tumors in African elephants ( N = 35). With a substantially more massive body and only slightly shorter lifespan than humans, the cancer mortality rate of elephants is lower than in humans. Elephants, with their natural cancer resistance, are exemplars of Peto’s Paradox-defined as the lack of correlation between lifespan, body size, and cancer risk across species. The lower threshold for DNA-damage-induced apoptosis in non-malignant cells correlates with the number of TP53 alleles. We previously reported that upon exposure to DNA damage, peripheral blood lymphocytes and fibroblasts from elephants undergo significantly more apoptosis compared to the same cells from healthy humans, and healthy human cells undergo significantly more apoptosis than cells from humans with a germline variant in one TP53 allele, i.e., Li-Fraumeni Syndrome. The expansion of TP53 copy number in the elephant genome may have occurred randomly or due to evolutionary pressure elucidating the function of an elephant TP53 retrogene would provide evolutionary insight into the potential cancer-protective role of these retrogenes. One TP53 allele is orthologous to other mammalian TP53 genes, whereas the other copies of elephant TP53 are retrogenes. Understanding the molecular mechanism by which the additional elephant TP53 retrogenes function may provide evolutionary insight that can be utilized for the development of therapeutics to treat human cancers.Īfrican and Asian elephants evolved ~20 additional TP53 genes in their genome. Our data show, for the first time, that expression of this truncated elephant p53 retrogene protein induces apoptosis in human cancer cells. At the mitochondria, p53-R9 binds to the pro-apoptotic BCL-2 family member Bax, which leads to caspase activation, cytochrome c release, and cell death. Tid1 expression is required for p53-R9-induced apoptosis. When expressed in human osteosarcoma cells (U2OS), p53-R9 binds to Tid1, the chaperone protein responsible for mitochondrial translocation of human p53 in response to cellular stress. This C-terminally truncated p53 retrogene protein lacks the nuclear localization signals and oligomerization domain of its full-length counterpart. Elephant TP53-RETROGENE 9 ( TP53-R9) encodes a p53 protein (p53-R9) that is truncated in the middle of the canonical DNA binding domain. Approximately 20 TP53 retrogenes exist in the African and Asian elephant genomes ( Loxodonta Africana, Elephas Maximus) in addition to a conserved TP53 gene that encodes a full-length protein.
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