Structural and mechanistic diversity in p53-mediated regulation of organismal longevity across taxonomical orders.
The link between p53 tumor suppressive functions and organismal lifespan is multifaceted. Its DNA-repair mechanism is longevity-enhancing while its role in cellular senescence pathways induces pro-aging phenotypes. To understand how p53 may regulate organismal lifespan, cross-species genotype-phenot...
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Public Library of Science (PLoS)
2025-05-01
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| Series: | PLoS Computational Biology |
| Online Access: | https://doi.org/10.1371/journal.pcbi.1012382 |
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| author | Romani Osbourne Kelly M Thayer |
| author_facet | Romani Osbourne Kelly M Thayer |
| author_sort | Romani Osbourne |
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| description | The link between p53 tumor suppressive functions and organismal lifespan is multifaceted. Its DNA-repair mechanism is longevity-enhancing while its role in cellular senescence pathways induces pro-aging phenotypes. To understand how p53 may regulate organismal lifespan, cross-species genotype-phenotype (GP) studies of the p53 DNA-binding domain (DBD) have been used to assess the correlation of amino acid changes to lifespan. Amino acid changes in non-DNA-binding regions such as the transactivation (TAD), proline-rich (PRD), regulatory (REG), and tetramerization (TET) are largely unexplored. In addition, existing GP correlation tools such as SigniSite do not account for phylogenetic relationships between aligned sequences in correlating genotypic differences to phenotypes such as lifespan. To identify phylogenetically significant, longevity-correlated residues in full-length p53 alignments, we developed a Python- and R-based workflow, Relative Evolutionary Scoring (RES). While RES-predicted longevity-associated residues (RPLARs) are concentrated primarily in the DBD, the PRD, TET, and REG domains also house RPLARs. While yeast functional assay enrichment reveals that RPLARs may be dispensable for p53-mediated transactivation, PEPPI and Rosetta-based protein-protein interaction prediction suggests a role for RPLARs in p53 stability and interaction interfaces of tumor suppressive protein-protein complexes. With experimental validation of the RPLARs' roles in p53 stability, transactivation, and involvement in senescence-regulatory pathways, we can gain crucial insights into mechanisms underlying dysregulated tumor suppression and accelerated aging. |
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| issn | 1553-734X 1553-7358 |
| language | English |
| publishDate | 2025-05-01 |
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| spelling | doaj-art-7e161e80efab43fa89ec2d34514379a12025-08-20T01:55:22ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582025-05-01215e101238210.1371/journal.pcbi.1012382Structural and mechanistic diversity in p53-mediated regulation of organismal longevity across taxonomical orders.Romani OsbourneKelly M ThayerThe link between p53 tumor suppressive functions and organismal lifespan is multifaceted. Its DNA-repair mechanism is longevity-enhancing while its role in cellular senescence pathways induces pro-aging phenotypes. To understand how p53 may regulate organismal lifespan, cross-species genotype-phenotype (GP) studies of the p53 DNA-binding domain (DBD) have been used to assess the correlation of amino acid changes to lifespan. Amino acid changes in non-DNA-binding regions such as the transactivation (TAD), proline-rich (PRD), regulatory (REG), and tetramerization (TET) are largely unexplored. In addition, existing GP correlation tools such as SigniSite do not account for phylogenetic relationships between aligned sequences in correlating genotypic differences to phenotypes such as lifespan. To identify phylogenetically significant, longevity-correlated residues in full-length p53 alignments, we developed a Python- and R-based workflow, Relative Evolutionary Scoring (RES). While RES-predicted longevity-associated residues (RPLARs) are concentrated primarily in the DBD, the PRD, TET, and REG domains also house RPLARs. While yeast functional assay enrichment reveals that RPLARs may be dispensable for p53-mediated transactivation, PEPPI and Rosetta-based protein-protein interaction prediction suggests a role for RPLARs in p53 stability and interaction interfaces of tumor suppressive protein-protein complexes. With experimental validation of the RPLARs' roles in p53 stability, transactivation, and involvement in senescence-regulatory pathways, we can gain crucial insights into mechanisms underlying dysregulated tumor suppression and accelerated aging.https://doi.org/10.1371/journal.pcbi.1012382 |
| spellingShingle | Romani Osbourne Kelly M Thayer Structural and mechanistic diversity in p53-mediated regulation of organismal longevity across taxonomical orders. PLoS Computational Biology |
| title | Structural and mechanistic diversity in p53-mediated regulation of organismal longevity across taxonomical orders. |
| title_full | Structural and mechanistic diversity in p53-mediated regulation of organismal longevity across taxonomical orders. |
| title_fullStr | Structural and mechanistic diversity in p53-mediated regulation of organismal longevity across taxonomical orders. |
| title_full_unstemmed | Structural and mechanistic diversity in p53-mediated regulation of organismal longevity across taxonomical orders. |
| title_short | Structural and mechanistic diversity in p53-mediated regulation of organismal longevity across taxonomical orders. |
| title_sort | structural and mechanistic diversity in p53 mediated regulation of organismal longevity across taxonomical orders |
| url | https://doi.org/10.1371/journal.pcbi.1012382 |
| work_keys_str_mv | AT romaniosbourne structuralandmechanisticdiversityinp53mediatedregulationoforganismallongevityacrosstaxonomicalorders AT kellymthayer structuralandmechanisticdiversityinp53mediatedregulationoforganismallongevityacrosstaxonomicalorders |