Recently, the quest for the mythical fountain of youth has produced extensive research programs that aim to extend the healthy lifespan of humans. Despite advances in our understanding of the aging process, the surprisingly extended lifespan and cancer resistance of some animal species remain unexplained. The p53 protein plays a crucial role in tumor suppression, tissue homeostasis, and aging. Long-lived, cancer-free African elephants have 20 copies of the TP53 gene, including 19 retrogenes (38 alleles), which are partially active, whereas humans possess only one copy of TP53 and have an estimated cancer mortality rate of 11-25%. The mechanism through which p53 contributes to the resolution of the Peto's paradox in Animalia remains vague. Thus, in this work, we took advantage of the available datasets and inspected the p53 amino acid sequence of phylogenetically related organisms that show variations in their lifespans. We discovered new correlations between specific amino acid deviations in p53 and the lifespans across different animal species. We found that species with extended lifespans have certain characteristic amino acid substitutions in the p53 DNA-binding domain that alter its function, as depicted from the Phenotypic Annotation of p53 Mutations, using the PROVEAN tool or SWISS-MODEL workflow. In addition, the loop 2 region of the human p53 DNA-binding domain was identified as the longest region that was associated with longevity. The 3D model revealed variations in the loop 2 structure in long-lived species when compared with human p53. Our findings show a direct association between specific amino acid residues in p53 protein, changes in p53 functionality, and the extended animal lifespan, and further highlight the importance of p53 protein in aging.

Center for Hematology and Regenerative Medicine Department of Medicine Huddinge Karolinska Institute SE 171 74 Stockholm Sweden

Department of Biology and Ecology Faculty of Science University of Ostrava 71000 Ostrava Czech Republic

Department of Physics Faculty of Science University of Ostrava Chittussiho 10 71000 Ostrava Czech Republic

Faculty of Chemistry University of Warsaw Pasteura 1 02 093 Warsaw Poland

Institute of Biophysics of the Czech Academy of Sciences 61265 Brno Czech Republic

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Whittemore K., Vera E., Martínez-Nevado E., Sanpera C., Blasco M.A. Telomere Shortening Rate Predicts Species Life Span. Proc. Natl. Acad. Sci. USA. 2019;116:15122–15127. doi: 10.1073/pnas.1902452116. PubMed DOI PMC

Hughes B.G., Hekimi S. Many Possible Maximum Lifespan Trajectories. Nature. 2017;546:E8. doi: 10.1038/nature22786. PubMed DOI

Barbi E., Lagona F., Marsili M., Vaupel J.W., Wachter K.W. The Plateau of Human Mortality: Demography of Longevity Pioneers. Science. 2018;360:1459–1461. doi: 10.1126/science.aat3119. PubMed DOI PMC

Hägg S., Jylhävä J. Sex Differences in Biological Aging with a Focus on Human Studies. eLife. 2021;10:e63425. doi: 10.7554/eLife.63425. PubMed DOI PMC

Harman D. Aging: A Theory Based on Free Radical and Radiation Chemistry. J. Gerontol. 1956;11:298–300. doi: 10.1093/geronj/11.3.298. PubMed DOI

Sohal R.S., Weindruch R. Oxidative Stress, Caloric Restriction, and Aging. Science. 1996;273:59–63. doi: 10.1126/science.273.5271.59. PubMed DOI PMC

Storci G., Carolis S.D., Papi A., Bacalini M.G., Gensous N., Marasco E., Tesei A., Fabbri F., Arienti C., Zanoni M., et al. Genomic Stability, Anti-Inflammatory Phenotype, and up-Regulation of the RNAseH2 in Cells from Centenarians. Cell Death Differ. 2019;26:1845–1858. doi: 10.1038/s41418-018-0255-8. PubMed DOI PMC

Campisi J. Senescent Cells, Tumor Suppression, and Organismal Aging: Good Citizens, Bad Neighbors. Cell. 2005;120:513–522. doi: 10.1016/j.cell.2005.02.003. PubMed DOI

Bennett W.P., Hussain S.P., Vahakangas K.H., Khan M.A., Shields P.G., Harris C.C. Molecular Epidemiology of Human Cancer Risk: Gene–Environment Interactions and p53 Mutation Spectrum in Human Lung Cancer. J. Pathol. 1999;187:8–18. doi: 10.1002/(SICI)1096-9896(199901)187:1<8::AID-PATH232>3.0.CO;2-Y. PubMed DOI

Kandoth C., McLellan M.D., Vandin F., Ye K., Niu B., Lu C., Xie M., Zhang Q., McMichael J.F., Wyczalkowski M.A. Mutational Landscape and Significance across 12 Major Cancer Types. Nature. 2013;502:333–339. doi: 10.1038/nature12634. PubMed DOI PMC

Levine A.J., Oren M. The First 30 Years of p53: Growing Ever More Complex. Nat. Rev. Cancer. 2009;9:749–758. doi: 10.1038/nrc2723. PubMed DOI PMC

Petitjean A., Mathe E., Kato S., Ishioka C., Tavtigian S.V., Hainaut P., Olivier M. Impact of Mutant p53 Functional Properties on Tp53 Mutation Patterns and Tumor Phenotype: Lessons from Recent Developments in the IARC Tp53 Database. Hum. Mutat. 2007;28:622–629. doi: 10.1002/humu.20495. PubMed DOI

Bray F., Ferlay J., Soerjomataram I., Siegel R.L., Torre L.A., Jemal A. Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. A Cancer J. Clin. 2018;68:394–424. doi: 10.3322/caac.21492. PubMed DOI

Timmis A., Townsend N., Gale C., Grobbee R., Maniadakis N., Flather M., Wilkins E., Wright L., Vos R., Bax J. European Society of Cardiology: Cardiovascular Disease Statistics 2017. Eur. Heart J. 2018;39:508–579. doi: 10.1093/eurheartj/ehx628. PubMed DOI

Schmidt-Kastner P.K., Jardine K., Cormier M., McBurney M.W. Absence of p53-Dependent Cell Cycle Regulation in Pluripotent Mouse Cell Lines. Oncogene. 1998;16:3003–3011. doi: 10.1038/sj.onc.1201835. PubMed DOI

Stiewe T., Haran T.E. How Mutations Shape p53 Interactions with the Genome to Promote Tumorigenesis and Drug Resistance. Drug Resist. Updates. 2018;38:27–43. doi: 10.1016/j.drup.2018.05.001. PubMed DOI

Levine A.J. p53, the Cellular Gatekeeper for Growth and Division. Cell. 1997;88:323–331. doi: 10.1016/S0092-8674(00)81871-1. PubMed DOI

Rufini A., Tucci P., Celardo I., Melino G. Senescence and Aging: The Critical Roles of p53. Oncogene. 2013;32:5129. doi: 10.1038/onc.2012.640. PubMed DOI

Sabapathy K., Lane D.P. Therapeutic Targeting of p53: All Mutants Are Equal, but Some Mutants Are More Equal than Others. Nat. Rev. Clin. Oncol. 2018;15:13. doi: 10.1038/nrclinonc.2017.151. PubMed DOI

Vousden K.H., Lane D.P. p53 in Health and Disease. Nat. Rev. Mol. Cell Biol. 2007;8:275–283. doi: 10.1038/nrm2147. PubMed DOI

Chen J. The Cell-Cycle Arrest and Apoptotic Functions of p53 in Tumor Initiation and Progression. Cold Spring Harb. Perspect. Med. 2016;6:a026104. doi: 10.1101/cshperspect.a026104. PubMed DOI PMC

Hafner A., Bulyk M.L., Jambhekar A., Lahav G. The Multiple Mechanisms That Regulate p53 Activity and Cell Fate. Nat. Rev. Mol. Cell Biol. 2019;20:199–210. doi: 10.1038/s41580-019-0110-x. PubMed DOI

Aubrey B.J., Kelly G.L., Janic A., Herold M.J., Strasser A. How Does p53 Induce Apoptosis and How Does This Relate to p53-Mediated Tumour Suppression? Cell Death Differ. 2018;25:104–113. doi: 10.1038/cdd.2017.169. PubMed DOI PMC

Pfaff M.J., Mukhopadhyay S., Hoofnagle M., Chabasse C., Sarkar R. Tumor Suppressor Protein p53 Negatively Regulates Ischemia-Induced Angiogenesis and Arteriogenesis. J. Vasc. Surg. 2018;68:222S–233S. doi: 10.1016/j.jvs.2018.02.055. PubMed DOI PMC

Nicolai S., Rossi A., Di Daniele N., Melino G., Annicchiarico-Petruzzelli M., Raschellà G. DNA Repair and Aging: The Impact of the p53 Family. Aging. 2015;7:1050. doi: 10.18632/aging.100858. PubMed DOI PMC

Itahana K., Dimri G., Campisi J. Regulation of Cellular Senescence by p53. Eur. J. Biochem. 2001;268:2784–2791. doi: 10.1046/j.1432-1327.2001.02228.x. PubMed DOI

Brázda V., Fojta M. The Rich World of p53 DNA Binding Targets: The Role of DNA Structure. Int. J. Mol. Sci. 2019;20:5605. doi: 10.3390/ijms20225605. PubMed DOI PMC

El-Deiry W.S., Kern S.E., Pietenpol J.A., Kinzler K.W., Vogelstein B. Definition of a Consensus Binding Site for p53. Nat. Genet. 1992;1:45–49. doi: 10.1038/ng0492-45. PubMed DOI

Vyas P., Beno I., Xi Z., Stein Y., Golovenko D., Kessler N., Rotter V., Shakked Z., Haran T.E. Diverse p53/DNA Binding Modes Expand the Repertoire of p53 Response Elements. Proc. Natl. Acad. Sci. USA. 2017;114:10624–10629. doi: 10.1073/pnas.1618005114. PubMed DOI PMC

Lane D.P. Cancer. p53, Guardian of the Genome. Nature. 1992;358:15–16. doi: 10.1038/358015a0. PubMed DOI

Toufektchan E., Toledo F. The Guardian of the Genome Revisited: p53 Downregulates Genes Required for Telomere Maintenance, DNA Repair, and Centromere Structure. Cancers. 2018;10:135. doi: 10.3390/cancers10050135. PubMed DOI PMC

Bartas M., Brázda V., Červeň J., Pečinka P. Characterization of p53 Family Homologs in Evolutionary Remote Branches of Holozoa. Int. J. Mol. Sci. 2020;21:6. doi: 10.3390/ijms21010006. PubMed DOI PMC

Belyi V.A., Levine A.J. One Billion Years of p53/P63/P73 Evolution. Proc. Natl. Acad. Sci. USA. 2009;106:17609–17610. doi: 10.1073/pnas.0910634106. PubMed DOI PMC

Engelmann D., Meier C., Alla V., Pützer B.M. A Balancing Act: Orchestrating Amino-Truncated and Full-Length P73 Variants as Decisive Factors in Cancer Progression. Oncogene. 2015;34:4287–4299. doi: 10.1038/onc.2014.365. PubMed DOI

Jiang L., Zawacka-Pankau J. The p53/MDM2/MDMX-Targeted Therapies—a Clinical Synopsis. Cell Death Dis. 2020;11:1–4. doi: 10.1038/s41419-020-2445-9. PubMed DOI PMC

Tyner S.D., Venkatachalam S., Choi J., Jones S., Ghebranious N., Igelmann H., Lu X., Soron G., Cooper B., Brayton C., et al. p53 Mutant Mice That Display Early Ageing-Associated Phenotypes. Nature. 2002;415:45–53. doi: 10.1038/415045a. PubMed DOI

Moore L., Lu X., Ghebranious N., Tyner S., Donehower L.A. Aging-Associated Truncated Form of p53 Interacts with Wild-Type p53 and Alters p53 Stability, Localization, and Activity. Mech. Ageing Dev. 2007;128:717–730. doi: 10.1016/j.mad.2007.10.011. PubMed DOI PMC

García-Cao I., García-Cao M., Martín-Caballero J., Criado L.M., Klatt P., Flores J.M., Weill J.-C., Blasco M.A., Serrano M. ’Super p53′mice Exhibit Enhanced DNA Damage Response, Are Tumor Resistant and Age Normally. EMBO J. 2002;21:6225–6235. doi: 10.1093/emboj/cdf595. PubMed DOI PMC

Lessel D., Wu D., Trujillo C., Ramezani T., Lessel I., Alwasiyah M.K., Saha B., Hisama F.M., Rading K., Goebel I. Dysfunction of the MDM2/p53 Axis Is Linked to Premature Aging. J. Clin. Investig. 2017;127:3598–3608. doi: 10.1172/JCI92171. PubMed DOI PMC

Gannon H.S., Donehower L.A., Lyle S., Jones S.N. Mdm2–p53 Signaling Regulates Epidermal Stem Cell Senescence and Premature Aging Phenotypes in Mouse Skin. Dev. Biol. 2011;353:1–9. doi: 10.1016/j.ydbio.2011.02.007. PubMed DOI PMC

Sahin E., DePinho R.A. Axis of Ageing: Telomeres, p53 and Mitochondria. Nat. Rev. Mol. Cell Biol. 2012;13:397–404. doi: 10.1038/nrm3352. PubMed DOI PMC

De Keizer P.L., Laberge R.-M., Campisi J. p53: Pro-Aging or pro-Longevity? Aging. 2010;2:377. doi: 10.18632/aging.100178. PubMed DOI PMC

Maier B., Gluba W., Bernier B., Turner T., Mohammad K., Guise T., Sutherland A., Thorner M., Scrable H. Modulation of Mammalian Life Span by the Short Isoform of p53. Genes Dev. 2004;18:306–319. doi: 10.1101/gad.1162404. PubMed DOI PMC

Olivares-Illana V., Fåhraeus R. p53 Isoforms Gain Functions. Oncogene. 2010;29:5113–5119. doi: 10.1038/onc.2010.266. PubMed DOI

De Magalhaes J.P., Costa J. A Database of Vertebrate Longevity Records and Their Relation to Other Life-History Traits. J. Evol. Biol. 2009;22:1770–1774. doi: 10.1111/j.1420-9101.2009.01783.x. PubMed DOI

Keane M., Semeiks J., Webb A.E., Li Y.I., Quesada V., Craig T., Madsen L.B., van Dam S., Brawand D., Marques P.I., et al. Insights into the Evolution of Longevity from the Bowhead Whale Genome. Cell Rep. 2015;10:112–122. doi: 10.1016/j.celrep.2014.12.008. PubMed DOI PMC

Edgar R.C. MUSCLE: Multiple Sequence Alignment with High Accuracy and High Throughput. Nucleic Acids Res. 2004;32:1792–1797. doi: 10.1093/nar/gkh340. PubMed DOI PMC

Deuter R., Müller O. Detection of APC Mutations in Stool DNA of Patients with Colorectal Cancer by HD-PCR. Hum. Mutat. 1998;11:84–89. doi: 10.1002/(SICI)1098-1004(1998)11:1<84::AID-HUMU13>3.0.CO;2-V. PubMed DOI

Pellegata N.S., Sessa F., Renault B., Bonato M., Leone B.E., Solcia E., Ranzani G.N. K-Ras and p53 Gene Mutations in Pancreatic Cancer: Ductal and Nonductal Tumors Progress through Different Genetic Lesions. Cancer Res. 1994;54:1556–1560. PubMed

Giacomelli A.O., Yang X., Lintner R.E., McFarland J.M., Duby M., Kim J., Howard T.P., Takeda D.Y., Ly S.H., Kim E. Mutational Processes Shape the Landscape of Tp53 Mutations in Human Cancer. Nat. Genet. 2018;50:1381. doi: 10.1038/s41588-018-0204-y. PubMed DOI PMC

Wilkinson G.S., South J.M. Life History, Ecology and Longevity in Bats. Aging Cell. 2002;1:124–131. doi: 10.1046/j.1474-9728.2002.00020.x. PubMed DOI

Kleiber M. Body Size and Metabolism. Hilgardia. 1932;6:315–353. doi: 10.3733/hilg.v06n11p315. DOI

Jessen L.E., Hoof I., Lund O., Nielsen M. SigniSite: Identification of Residue-Level Genotype-Phenotype Correlations in Protein Multiple Sequence Alignments. Nucleic Acids Res. 2013;41:W286–W291. doi: 10.1093/nar/gkt497. PubMed DOI PMC

Olivier M., Eeles R., Hollstein M., Khan M.A., Harris C.C., Hainaut P. The IARC Tp53 Database: New Online Mutation Analysis and Recommendations to Users. Hum. Mutat. 2002;19:607–614. doi: 10.1002/humu.10081. PubMed DOI

Passow C.N., Bronikowski A.M., Blackmon H., Parsai S., Schwartz T.S., McGaugh S.E. Contrasting Patterns of Rapid Molecular Evolution within the p53 Network across Mammal and Sauropsid Lineages. Genome Biol. Evol. 2019;11:629–643. doi: 10.1093/gbe/evy273. PubMed DOI PMC

Ong A.L.C., Ramasamy T.S. Role of Sirtuin1-p53 Regulatory Axis in Aging, Cancer and Cellular Reprogramming. Ageing Res. Rev. 2018;43:64–80. doi: 10.1016/j.arr.2018.02.004. PubMed DOI

Liu J., Guan D., Dong M., Yang J., Wei H., Liang Q., Song L., Xu L., Bai J., Liu C., et al. UFMylation Maintains Tumour Suppressor p53 Stability by Antagonizing Its Ubiquitination. Nat. Cell Biol. 2020;22:1056–1063. doi: 10.1038/s41556-020-0559-z. PubMed DOI

Qian Y., Chen X. Senescence Regulation by the p53 Protein Family. Cell Senescence. 2013;9:37–61. doi: 10.1007/978-1-62703-239-1_3. PubMed DOI PMC

Soussi T., Wiman K.G. Tp53: An Oncogene in Disguise. Cell Death Differ. 2015;22:1239–1249. doi: 10.1038/cdd.2015.53. PubMed DOI PMC

Kubota S. Repeating Rejuvenation in Turritopsis, an Immortal Hydrozoan (Cnidaria, Hydrozoa) Biogeography. 2011;12:101–103.

Hasegawa Y., Watanabe T., Takazawa M., Ohara O., Kubota S. De Novo Assembly of the Transcriptome of Turritopsis, a Jellyfish That Repeatedly Rejuvenates. Zool. Sci. 2016;33:366–372. doi: 10.2108/zs150186. PubMed DOI

Choi Y., Chan A.P. PROVEAN Web Server: A Tool to Predict the Functional Effect of Amino Acid Substitutions and Indels. Bioinformatics. 2015;31:2745–2747. doi: 10.1093/bioinformatics/btv195. PubMed DOI PMC

Lukman S., Lane D.P., Verma C.S. Mapping the Structural and Dynamical Features of Multiple p53 DNA Binding Domains: Insights into Loop 1 Intrinsic Dynamics. PLoS ONE. 2013;8:e80221. doi: 10.1371/journal.pone.0080221. PubMed DOI PMC

Linnér R.K., Biroli P., Kong E., Meddens S.F.W., Wedow R., Fontana M.A., Lebreton M., Tino S.P., Abdellaoui A., Hammerschlag A.R. Genome-Wide Association Analyses of Risk Tolerance and Risky Behaviors in over 1 Million Individuals Identify Hundreds of Loci and Shared Genetic Influences. Nat. Genet. 2019;51:245–257. doi: 10.1038/s41588-018-0309-3. PubMed DOI PMC

Berkel C., Cacan E. Analysis of Longevity in Chordata Identifies Species with Exceptional Longevity among Taxa and Points to the Evolution of Longer Lifespans. Biogerontology. 2021;22:329–343. doi: 10.1007/s10522-021-09919-w. PubMed DOI

Arum O., Johnson T.E. Reduced Expression of the Caenorhabditis Elegans p53 Ortholog Cep-1 Results in Increased Longevity. J. Gerontol. Ser. Biol. Sci. Med. Sci. 2007;62:951–959. doi: 10.1093/gerona/62.9.951. PubMed DOI

Bauer J.H., Poon P.C., Glatt-Deeley H., Abrams J.M., Helfand S.L. Neuronal Expression of p53 Dominant-Negative Proteins in Adult Drosophila Melanogaster Extends Life Span. Curr. Biol. 2005;15:2063–2068. doi: 10.1016/j.cub.2005.10.051. PubMed DOI

Bonafè M., Olivieri F., Mari D., Baggio G., Mattace R., Sansoni P., De Benedictis G., De Luca M., Bertolini S., Barbi C. p53 Variants Predisposing to Cancer Are Present in Healthy Centenarians. Am. J. Hum. Genet. 1999;64:292. doi: 10.1086/302196. PubMed DOI PMC

Van Heemst D., Mooijaart S.P., Beekman M., Schreuder J., de Craen A.J.M., Brandt B.W., Eline Slagboom P., Westendorp R.G.J. Variation in the Human Tp53 Gene Affects Old Age Survival and Cancer Mortality. Exp. Gerontol. 2005;40:11–15. doi: 10.1016/j.exger.2004.10.001. PubMed DOI

Zhao Y., Wu L., Yue X., Zhang C., Wang J., Li J., Sun X., Zhu Y., Feng Z., Hu W. A Polymorphism in the Tumor Suppressor p53 Affects Aging and Longevity in Mouse Models. Elife. 2018;7:e34701. doi: 10.7554/eLife.34701. PubMed DOI PMC

Sulak M., Fong L., Mika K., Chigurupati S., Yon L., Mongan N.P., Emes R.D., Lynch V.J. Tp53 Copy Number Expansion Is Associated with the Evolution of Increased Body Size and an Enhanced DNA Damage Response in Elephants. Elife. 2016;5:e11994. doi: 10.7554/eLife.11994. PubMed DOI PMC

Tejada-Martinez D., de Magalhães J.P., Opazo J.C. Positive Selection and Gene Duplications in Tumour Suppressor Genes Reveal Clues about How Cetaceans Resist Cancer. Proc. R. Soc. B Biol. Sci. 2021;288:20202592. doi: 10.1098/rspb.2020.2592. PubMed DOI PMC

Deuker M.M., Lewis K.N., Ingaramo M., Kimmel J., Buffenstein R., Settleman J. Unprovoked Stabilization and Nuclear Accumulation of the Naked Mole-Rat p53 Protein. Sci. Rep. 2020;10:6966. doi: 10.1038/s41598-020-64009-0. PubMed DOI PMC

Boughey H., Jurga M., El-Khamisy S.F. DNA Homeostasis and Senescence: Lessons from the Naked Mole Rat. Int. J. Mol. Sci. 2021;22:6011. doi: 10.3390/ijms22116011. PubMed DOI PMC

Bai G.-L., Wang P., Huang X., Wang Z.-Y., Cao D., Liu C., Liu Y.-Y., Li R.-L., Chen A.-J. Rapamycin Protects Skin Fibroblasts from UVA-Induced Photoaging by Inhibition of p53 and Phosphorylated HSP27. Front. Cell Dev. Biol. 2021;9:134. doi: 10.3389/fcell.2021.633331. PubMed DOI PMC

Frey K., Hafner A., Pucker B. The Reuse of Public Datasets in the Life Sciences: Potential Risks and Rewards. Peer J. 2020;22:e9954. doi: 10.7717/peerj.9954. PubMed DOI PMC

Okonechnikov K., Golosova O., Fursov M., Team U. Unipro UGENE: A Unified Bioinformatics Toolkit. Bioinformatics. 2012;28:1166–1167. doi: 10.1093/bioinformatics/bts091. PubMed DOI

Grabherr M.G., Haas B.J., Yassour M., Levin J.Z., Thompson D.A., Amit I., Adiconis X., Fan L., Raychowdhury R., Zeng Q. Full-Length Transcriptome Assembly from RNA-Seq Data without a Reference Genome. Nat. Biotechnol. 2011;29:644. doi: 10.1038/nbt.1883. PubMed DOI PMC

Afgan E., Baker D., Batut B., Van Den Beek M., Bouvier D., Čech M., Chilton J., Clements D., Coraor N., Grüning B.A. The Galaxy Platform for Accessible, Reproducible and Collaborative Biomedical Analyses: 2018 Update. Nucleic Acids Res. 2018;46:W537–W544. doi: 10.1093/nar/gky379. PubMed DOI PMC

Dereeper A., Guignon V., Blanc G., Audic S., Buffet S., Chevenet F., Dufayard J.-F., Guindon S., Lefort V., Lescot M. Phylogeny. Fr: Robust Phylogenetic Analysis for the Non-Specialist. Nucleic Acids Res. 2008;36:W465–W469. doi: 10.1093/nar/gkn180. PubMed DOI PMC

Dereeper A., Audic S., Claverie J.-M., Blanc G. BLAST-EXPLORER Helps You Building Datasets for Phylogenetic Analysis. BMC Evol. Biol. 2010;10:8. doi: 10.1186/1471-2148-10-8. PubMed DOI PMC

Castresana J. Selection of Conserved Blocks from Multiple Alignments for Their Use in Phylogenetic Analysis. Mol. Biol. Evol. 2000;17:540–552. doi: 10.1093/oxfordjournals.molbev.a026334. PubMed DOI

Anisimova M., Gascuel O. Approximate Likelihood-Ratio Test for Branches: A Fast, Accurate, and Powerful Alternative. Syst. Biol. 2006;55:539–552. doi: 10.1080/10635150600755453. PubMed DOI

Guindon S., Gascuel O. A Simple, Fast, and Accurate Algorithm to Estimate Large Phylogenies by Maximum Likelihood. Syst. Biol. 2003;52:696–704. doi: 10.1080/10635150390235520. PubMed DOI

Chevenet F., Brun C., Bañuls A.-L., Jacq B., Christen R. TreeDyn: Towards Dynamic Graphics and Annotations for Analyses of Trees. BMC Bioinform. 2006;7:439. doi: 10.1186/1471-2105-7-439. PubMed DOI PMC

Letunic I., Bork P. Interactive Tree Of Life (ITOL) v4: Recent Updates and New Developments. Nucleic Acids Res. 2019;47:W256–W259. doi: 10.1093/nar/gkz239. PubMed DOI PMC

Choi Y., Sims G.E., Murphy S., Miller J.R., Chan A.P. Predicting the Functional Effect of Amino Acid Substitutions and Indels. PLoS ONE. 2012;7:e46688. doi: 10.1371/journal.pone.0046688. PubMed DOI PMC

Waterhouse A., Bertoni M., Bienert S., Studer G., Tauriello G., Gumienny R., Heer F.T., de Beer T.A.P., Rempfer C., Bordoli L., et al. SWISS-MODEL: Homology Modelling of Protein Structures and Complexes. Nucleic Acids Res. 2018;46:W296–W303. doi: 10.1093/nar/gky427. PubMed DOI PMC

Emamzadah S., Tropia L., Vincenti I., Falquet B., Halazonetis T.D. Reversal of the DNA-Binding-Induced Loop L1 Conformational Switch in an Engineered Human p53 Protein. J. Mol. Biol. 2014;426:936–944. doi: 10.1016/j.jmb.2013.12.020. PubMed DOI

Pettersen E.F., Goddard T.D., Huang C.C., Couch G.S., Greenblatt D.M., Meng E.C., Ferrin T.E. UCSF Chimera—a Visualization System for Exploratory Research and Analysis. J. Comput. Chem. 2004;25:1605–1612. doi: 10.1002/jcc.20084. PubMed DOI

Källberg M., Wang H., Wang S., Peng J., Wang Z., Lu H., Xu J. Template-Based Protein Structure Modeling Using the RaptorX Web Server. Nat. Protoc. 2012;7:1511–1522. doi: 10.1038/nprot.2012.085. PubMed DOI PMC

Simonetti F.L., Teppa E., Chernomoretz A., Nielsen M., Marino Buslje C. MISTIC: Mutual Information Server to Infer Coevolution. Nucleic Acids Res. 2013;41:W8–W14. doi: 10.1093/nar/gkt427. PubMed DOI PMC

Herrero J., Muffato M., Beal K., Fitzgerald S., Gordon L., Pignatelli M., Vilella A.J., Searle S.M., Amode R., Brent S. Ensembl Comparative Genomics Resources. Database. 2016;2016:96. doi: 10.1093/database/baw053. PubMed DOI PMC

Thermal stress, p53 structures and learning from elephants

Impacts of Molecular Structure on Nucleic Acid-Protein Interactions

The Elephant Evolved p53 Isoforms that Escape MDM2-Mediated Repression and Cancer