Genetic instability induced by hypoxic stress

Abstract

Lack of sufficient oxygen, known as hypoxia, constitutes a significant physiological stress, particularly relevant to cancer biology. In similarity to many other stresses, hypoxia induces an integrated response that both adapts cellular machinery to the stress and generates genomic instability, which can promote accelerated genetic evolution. The cellular response to hypoxia, mediated by hypoxia - inducible factor (HIF) signaling and HIF-independent signaling pathways, drives changes in metabolism, oxygen supply, and cell growth. In concert with these adaptations, genetic instability occurs through the down-regulation of DNA repair pathways-particularly nucleotide excision repair, mismatch repair, and homologous recombination repair- and increased DNA damage rates, especially during reoxygenation. To prevent mutagenesis, cells respond to DNA damage with the activation of cell cycle checkpoints and apoptotic pathways, which thus interconnect closely with the hypoxic stress response. As a pervasive feature of solid tumors, hypoxia may promote cancer progression through its impact on genomic integrity.