| Summary: | The <i>TP53</i> gene is a major player in cancer formation, and it is considered the most important tumor suppressor gene. The p53 protein acts as a transcription factor, and it is involved in DNA repair, senescence, cell-cycle control, autophagy, and apoptosis. Beyond cancer, there is evidence that <i>TP53</i> is associated with fertility, aging, and longevity. Additionally, more evidence exists that genetic variants in <i>TP53</i> are associated with environmental adaptation. Special <i>TP53</i> amino-acid residues or pathogenic <i>TP53</i> mutations seem to be adaptive for animals living in hypoxic and cold environments or having been exposed to starvation, respectively. At the somatic level, it has recently been proven that multiple cancer genes, including <i>TP53</i>, are under positive selection in healthy human tissues. It is not clear why these driver mutations do not transform these tissues into cancerous ones. Other studies have shown that elephants have multiple <i>TP53</i> copies, probably this being the reason for the very low cancer incidence in these large animals. This may explain the famous Peto’s paradox. This review discusses in detail the multilevel role of <i>TP53</i> in adaptation, according to the published evidence. This role is complicated, and it extends from cells to individuals and to populations.
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