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The plateau zokor (Myospalax baileyi) is a specialized subterranean rodent that lives on the Qinghai-Tibet Plateau. The species has evolved a series of strategies to adapt to its hypoxic environment and hypercapnia. p53 is a tumour suppressor gene that plays a crucial role in the cellular response to hypoxia by inducing cell cycle arrest, cell apoptosis, DNA damage repair and angiogenesis. To investigate the sequence characteristics of p53 and the response to hypoxia in plateau zokor, we cloned the p53 coding DNA sequence, analysed it, and measured the expression level of p53 at different altitudes in plateau zokor and rats. Our results show that the coding DNA sequence is 1179 bp, consisting of 392 amino acid residues. Compared to human p53, the subterranean rodents have two mutation sites in common with the human hotspots in the DNA-binding domain. Compared to subterranean rodents, plateau zokor have a mutation at residue 309. In addition, subterranean rodents have two convergent sites at residues 78 and 84. The expression levels of p53 in plateau zokor tissues increase significantly from 2260 m to 3300 m, but there was no significant difference in rats at those altitudes. Our results suggest that subterranean rodents have two mutation sites in common with the human hotspots in the DNA-binding domain, the mutation of Gly309Asp is a unique mutation site of plateau zokor p53, and there are two convergent sites enhancing subterranean rodent adaptation to hypoxic conditions. In addition, p53 is sensitive to the oxygen concentration in plateau zokor, and hypoxia upregulates the levels of p53. Generally, plateau zokor use this strategy to adapt to a hypoxic environment.