DNA damage response (DDR) pathways in hypoxic tumor cells (DDR in hypoxia)

DNA damage response (DDR) pathways in hypoxic tumor cells represent a complex network of signaling and repair mechanisms that are significantly altered by the low-oxygen microenvironment characteristic of solid tumors (PMID: 25486332). Hypoxia typically suppresses high-fidelity DNA repair pathways, such as homologous recombination (HR) and mismatch repair (MMR), while inducing a state of functional "BRCAness" that increases genomic instability and promotes tumor progression (PMID: 30333115). This metabolic and physiological stress activates key kinases like ATM and ATR, even in the absence of exogenous DNA damage, to manage replication stress (Nature Reviews Cancer, 2011). From a therapeutic perspective, the downregulation of HR in hypoxic cells makes them selectively vulnerable to PARP inhibitors and other DDR-targeting agents, a strategy known as synthetic lethality (PMID: 28611164). Furthermore, targeting these pathways is a critical approach to overcoming the radioresistance and chemoresistance typically associated with hypoxic niches in aggressive cancers (PMID: 32154405).

Other names

Hypoxia-induced DNA damage responseDDR in hypoxic microenvironmentHypoxic DDR

Inhibition of DNA repair enzymes (e.g., PARP, ATR, ATM) to exploit hypoxia-induced repair deficiencies (synthetic lethality) or to sensitize hypoxic cells to DNA-damaging radiotherapy and chemotherapy.