title: Adaptive patterns in the p53 protein sequence of the hypoxia- and cancer-tolerant blind mole rat Spalax.
abstract: The subterranean blind mole rat, Spalax (genus Nannospalax) endures extreme hypoxic conditions and fluctuations in oxygen levels that threaten DNA integrity. Nevertheless, Spalax is long-lived, does not develop spontaneous cancer, and exhibits an outstanding resistance to carcinogenesis in vivo, as well as anti-cancer capabilities in vitro. We hypothesized that adaptations to similar extreme environmental conditions involve common mechanisms for overcoming stress-induced DNA damage. Therefore, we aimed to identify shared features among species that are adapted to hypoxic stress in the sequence of the tumor-suppressor protein p53, a master regulator of the DNA-damage response (DDR).
  
  
  
  We found that the sequences of p53 transactivation subdomain 2 (TAD2) and tetramerization and regulatory domains (TD and RD) are more similar among hypoxia-tolerant species than expected from phylogeny. Specific positions in these domains composed patterns that are more frequent in hypoxia-tolerant species and have proven to be good predictors of species' classification into stress-related categories. Some of these positions, which are known to be involved in the interactions between p53 and critical DDR proteins, were identified as positively selected. By 3D modeling of p53 interactions with the coactivator p300 and the DNA repair protein RPA70, we demonstrated that, compared to humans, these substitutions potentially reduce the binding of these proteins to Spalax p53.
  
  
  
  We conclude that extreme hypoxic conditions may have led to convergent evolutionary adaptations of the DDR via TAD2 and TD/RD domains of p53.
authors: Institute of Evolution & Department of Evolutionary and Environmental Biology, University of Haifa, Haifa, Israel.
authors: Vered
authors: V
authors: Domankevich
authors: Mina and Everard Goodman Faculty of Life Sciences and Advanced Materials and Nanotechnology Institute, Bar-Ilan University, Ramat-Gan, Israel.
authors: Yarden
authors: Y
authors: Opatowsky
authors: Institute of Evolution & Department of Evolutionary and Environmental Biology, University of Haifa, Haifa, Israel.
authors: Assaf
authors: A
authors: Malik
authors: Institute of Evolution & Department of Evolutionary and Environmental Biology, University of Haifa, Haifa, Israel.
authors: Abraham B
authors: AB
authors: Korol
authors: Institute of Evolution & Department of Evolutionary and Environmental Biology, University of Haifa, Haifa, Israel.
authors: Zeev
authors: Z
authors: Frenkel
authors: Institute of Evolution & Department of Evolutionary and Environmental Biology, University of Haifa, Haifa, Israel.
authors: Irena
authors: I
authors: Manov
authors: Institute of Evolution & Department of Evolutionary and Environmental Biology, University of Haifa, Haifa, Israel.
authors: Aaron
authors: A
authors: Avivi
authors: Institute of Evolution & Department of Evolutionary and Environmental Biology, University of Haifa, Haifa, Israel. imad.shams@univ.haifa.ac.il.
authors: Imad
authors: I
authors: Shams
mesh_terms: D000222:Adaptation, Physiological; D000595:Amino Acid Sequence; D000818:Animals; D005075:Biological Evolution; D004260:DNA Repair; D000860:Hypoxia / Q000662:veterinary; D008958:Models, Molecular; D009369:Neoplasms / Q000235:genetics / Q000662:veterinary; D010100:Oxygen / Q000378:metabolism; D016415:Sequence Alignment; D046308:Spalax / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; D010100:Oxygen
keywords: Cancer resistance; Convergent evolution; Hypoxia; Longevity; Oxidative stress; P53; RPA70; TAD2