Structural and mechanistic diversity in p53-mediated regulation of organismal longevity across taxonomical orders

Abstract The accumulation of senescent cells induces several aging phenotypes, and the p53 tumor suppressor protein regulates one of the two known cellular senescence pathways. p53’s regulation of senescence is however not clear. For example, p53 deficiency in some mice has been shown to rescue premature aging while others display significant aging phenotype when p53-deficient. This study seeks to elucidate, structurally and mechanistically, p53’s roles in longevity. Through a relative evolutionary scoring (RES) algorithm, we quantify the level of evolutionary change in the residues of p53 across organisms of varying average lifespans in six taxonomic orders. Secondly, we used PEPPI to assess the likelihood of interaction between p53–or p53-linked proteins–and known senescence-regulating proteins across organisms in the orders Primates and Perciformes. Our RES algorithm found variations in the alignments within and across orders, suggesting that mechanisms of p53-mediated regulation of longevity may vary. PEPPI results suggest that longer-lived species may have evolved to regulate induction and inhibition of cellular senescence better than their shorter-lived counterparts. With experimental verification, these predictions could help elucidate the mechanisms of p53-mediated cellular senescence, ultimately clarifying our understanding of p53’s connection to aging in a multiple-species context. Author summary The p53 tumor suppressor protein protects our genome from cancers by repairing DNA damage, regulating cell death and/or pushing cells to a state where they become permanently unable to divide (known as cellular senescence). An accumulation of senescent cells produces various molecular features of aging in both mouse and human cellular models–thus linking p53 to the aging process. However, the molecular mechanism by which p53 regulates aging and its structural implications on this regulation are not clear. In this study, we assessed quantitatively the evolutionary differences in p53 sequences of organisms across several taxonomical orders to determine if there is a relationship between average lifespan and sequence evolution. In addition, we used a protein-protein interaction tool to assess the likelihood of interaction between p53, or p53-associated protein, and various senescence-associated proteins across organisms of various lifespans in two taxonomic orders: Primates and Perciformes. An elucidation of p53 structural difference and mechanistic proteomic network linked to p53 regulation of cellular senescence could advance therapeutics targeting abnormal aging.