As species adapt to climatic changes, temperature-dependent functions of p53 in development, metabolism and cancer will adapt as well. Structural analyses of p53 epitopes interacting in response to environmental stressors, such as heat, may uncover physiologically relevant functions of p53 in cell regulation and genomic adaptations. Here we explore the multiple p53 elephant paradigm with an experimentally validated in silico model showing that under heat stress some p53 copies escape negative regulation by the MDM2 E3 ubiquitin ligase. Multiple p53 isoforms have evolved naturally in the elephant thus presenting a unique experimental system to study the scope of p53 functions and the contribution of environmental stressors to DNA damage. We assert that fundamental insights derived from studies of a historically heat-challenged mammal will provide important insights directly relevant to human biology in the light of climate change when 'heat' may introduce novel challenges to our bodies and health.

Department of Biology University of Oxford Oxford UK

Department of Medical Biosciences Umeå University Umeå Sweden

Inserm UMRS1131 Institut de Génétique Moléculaire Université Paris 7 Hôpital St Louis Paris France

Institut de Biotecnologia i de Biomedicina Universitat Autònoma de Barcelona Bellaterra Barcelona Spain

International Centre for Cancer Vaccine Science University of Gdansk ul Kładki 24 Gdansk Poland

Research Centre for Applied Molecular Oncology Masaryk Memorial Cancer Institute Brno Czech Republic

Save the Elephants Marula Manor Karen P O Box 54667 Nairobi Kenya

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