Adaptive patterns in the p53 protein sequence of the hypoxia- and cancer-tolerant blind mole rat Spalax

BMC Evolutionary Biology

Research Article

Aaron Avivi¹  Abraham B. Korol¹  Imad Shams¹  Vered Domankevich¹  Zeev Frenkel¹  Irena Manov¹  Assaf Malik¹  Yarden Opatowsky² 

[1] Institute of Evolution & Department of Evolutionary and Environmental Biology, University of Haifa, Haifa, Israel;Mina and Everard Goodman Faculty of Life Sciences and Advanced Materials and Nanotechnology Institute, Bar-Ilan University, Ramat-Gan, Israel;

关键词: P53;    Hypoxia;    Oxidative stress;    RPA70;    TAD2;    Convergent evolution;    Cancer resistance;    Longevity;   

DOI  :  10.1186/s12862-016-0743-8

 received in 2015-11-18, accepted in 2016-08-17,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundThe 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).ResultsWe 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.ConclusionsWe conclude that extreme hypoxic conditions may have led to convergent evolutionary adaptations of the DDR via TAD2 and TD/RD domains of p53.

【 授权许可】

CC BY   
© The Author(s). 2016