Hypoxic Stress Perturb DNA Repair Mechanisms Leading to Genetic Instability

Hypoxia contributes to the growth and development of the tumors by facilitating the formation of stem cells, epithelial to mesenchymal transition, heterogeneity, and immune escape. Hypoxia inducible factors (HIF-1α and HIF-1β) regulate several mechanisms like cell survival, proliferation, metabolism, pH regulation, and angiogenesis in the tumor microenvironment. Currently, we understand that genomic instability leads to accumulation of mutations and contributes to heterogeneity and evolution, metastases, and resistance to treatment. Hypoxia contributes to genomic instability in several ways. Tumor hypoxia downregulate the DNA damage and repair pathways at transcriptional and translational level. Hypoxia induced reduction in nucleotide availability can lead to replication stress. In addition, hypoxia exerts selectional pressure on genetically transformed cells and is one of the causative factor for genetic heterogeneity. Hence understanding the functionality of DNA damage response and repair mechanisms play an important role in deciphering the key properties of tumor development under hypoxic conditions. In this chapter, we discuss about the influence of hypoxia on the DNA damage response and the key DNA repair pathways, oxidative stress, replication control, and plethora of genetic changes that arise in the cellular model systems.