Molecular evolution of antioxidant and hypoxia response in long-lived, cancer-resistant blind mole rats: The Nrf2-Keap1 pathway

The Nrf2-Keap1 pathway is crucial for the cellular antioxidant and hypoxia response in vertebrates. Deciphering its modifications in hypoxia-adapted animals will help understand its functionality under environmental stress and possibly allow for knowledge transfer into biomedical research. The blind mole rat Spalax, a long-lived cancer-resistant rodent, lives in burrows underground and is adapted to severely hypoxic conditions. Here we have conducted a bioinformatical survey of Spalax core genes from the Nrf2-Keap1 pathway on the coding sequence level in comparison to other hypoxia-tolerant and -sensitive rodents. We find strong sequence conservation across all genes, illustrating the pathway's importance. One of the central players however, Spalax Keap1, shows a non-conservative amino acid substitution from tyrosine to cysteine in its intervening region (IVR) domain. Cysteines in this location have been shown to be of high functional relevance to the binding and degradation of Nrf2. Therefore, this peculiar substitution could influence the cellular Nrf2 levels in Spalax and, thereby, downstream gene expression in the antioxidant pathway, contributing to the special adaptive phenotype of the blind mole rat.