The tumor suppressor protein p53, encoded by the gene TP53, is thought to be a component of the trade-off between tissue maintenance and cancer risk that contributes to species life span. Too much p53 activity and cancer risk declines but life span shortens as tissue maintenance is also suppressed. To little p53 activity and life span increases, but so does cancer risk - eventually to the point of cutting short that extended life. Evolution comes to some balance for any given niche, but perhaps there is something to be learned from other species that could inform possible approaches to the control of cancer in our own species.
Several molecular mechanisms have been purported to regulate aging and influence lifespan - many of which have been linked to p53 tumor suppressor activities. In low or high-stress conditions, p53 binds to several target genes and induces tumor-suppressive processes such as DNA repair, apoptosis, and cellular senescence. In a context-dependent manner, its DNA-repair mechanism enhances longevity while aberrant apoptosis and cellular senescence accelerate aging.
Genotype-phenotype correlation studies that have sought to map observed differences in lifespan across species to differences in the sequence and structure of p53 ortholog have largely focused on the DNA-binding domain (DBD). For closely related p53 orthologs, those of longer-lived species possess unique mutations in their DBD that have been hypothesized to enhance their longevity-regulating interactome. Residues 180-192, which compose the L2 region of the DBD in human p53, are most highly correlated with longevity.
Amino acid changes in non-DNA-binding regions such as the transactivation (TAD), proline-rich (PRD), regulatory (REG), and tetramerization (TET) domains are largely unexplored. To address this, we developed a Relative Evolutionary Scoring (RES) workflow to comprehensively investigate the changes in full-length p53 structure across organisms of various taxonomic orders and observed average lifespan. Using the Sorting Intolerant From Tolerant (SIFT) mutation prediction tool and the results from yeast-based functional assays, we characterized the effect of found RES-predicted longevity-associated residues (RPLARs) on p53 function and tumor-suppressive pathways.
Our findings reveal that while most longevity-associated residues are found in the DNA-binding domain, critical residues also exist in other p53 domains. Mutational functional experiments and protein interaction predictions suggest these residues may play a vital role in p53 stability and its interactions with other proteins involved in the induction of senescence. This work broadens our understanding of the mechanisms undergirding dysregulated p53 tumor suppression and its link to accelerated aging.
Link: https://doi.org/10.1371/journal.pcbi.1012382
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