DNA damage response pathways (DDR)

The DNA damage response (DDR) is a sophisticated network of signaling and repair pathways that safeguard the integrity of the genome against endogenous and exogenous insults [1, 2]. It comprises several specialized mechanisms, such as base excision repair (BER), nucleotide excision repair (NER), and double-strand break repair (homologous recombination and non-homologous end joining), which are regulated by key kinases like ATM, ATR, and DNA-PK [3, 15]. In many cancers, specific DDR components are mutated or lost, leading to genomic instability—a hallmark of malignancy—while simultaneously creating a dependency on alternative repair pathways [12, 17]. This vulnerability is exploited by DDR inhibitors, such as PARP inhibitors, through the principle of synthetic lethality, particularly in tumors with BRCA1/2 deficiencies [5, 6]. Beyond their use as single agents, DDR-targeted therapies are increasingly investigated for their ability to sensitize cancer cells to radiotherapy and conventional chemotherapy [9, 12]. They also show promise in enhancing the efficacy of immune checkpoint inhibitors by increasing tumor mutational burden and neoantigen presentation [7, 8]. Furthermore, DDR dysfunction is a key driver in other conditions, including neurodegenerative diseases, immunodeficiencies, and premature aging syndromes [13, 16]. Therapeutic challenges include the development of resistance through mechanisms like reversion mutations and the potential for hematological toxicities [11, 18].

Other names

DNA damage responseDNA repair pathwaysDDR systemGenome integrity maintenance system

DDR-targeted drugs primarily act by inhibiting key repair enzymes or checkpoint kinases, leading to the accumulation of DNA damage and subsequent cell death, often through synthetic lethality in repair-deficient backgrounds or by sensitizing cells to exogenous DNA-damaging agents [1, 3, 17].