DNA damage response (DDR) pathway (DDR)

The DNA damage response (DDR) and repair machinery is a sophisticated network of signaling pathways and enzymatic processes dedicated to detecting, signaling, and repairing DNA lesions to maintain genomic stability [1][2]. This machinery encompasses several specialized pathways, including base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), and double-strand break repair mechanisms such as homologous recombination (HR) and non-homologous end joining (NHEJ) [2][3]. In many cancers, specific components of the DDR are mutated or epigenetically silenced, which drives genomic instability and tumor evolution but also creates unique therapeutic vulnerabilities [4]. Modern oncology exploits these defects through the principle of synthetic lethality, most notably with Poly(ADP-ribose) polymerase (PARP) inhibitors that are lethal to cells with pre-existing HR deficiencies, such as those with BRCA1/2 mutations [1][5]. Beyond PARP, the DDR machinery is targeted by inhibitors of key signaling kinases like Ataxia telangiectasia mutated (ATM), Ataxia telangiectasia and Rad3-related (ATR), and DNA-dependent protein kinase (DNA-PK) to enhance the efficacy of DNA-damaging therapies [4][6]. Understanding the DDR is critical for patient stratification, as biomarkers like HRD status determine the clinical utility of these targeted agents [5].

Other names

DNA damage response and repair (DDRR) machineryDNA repair systemGenome integrity maintenance systemDNA damage signaling and repair network

Inhibition of specific DNA repair enzymes or signaling kinases to induce synthetic lethality in repair-deficient cells or to sensitize tumors to DNA-damaging agents like chemotherapy and radiation.