Deoxyribonucleic acid and DNA repair machinery (DNA/DDR)

Deoxyribonucleic acid (DNA) and its associated repair machinery represent a critical therapeutic axis in oncology and genetic medicine. DNA serves as the primary blueprint for cellular function, while the repair machinery—comprising pathways like homologous recombination, non-homologous end joining, and base excision repair—ensures genomic integrity against endogenous and exogenous damage (Lord & Ashworth, 2012, Nature). Traditional chemotherapies, such as platinum agents and alkylating drugs, target DNA directly to induce cytotoxic lesions that overwhelm the cell's ability to replicate (Puccini et al., 2022, CA: A Cancer Journal for Clinicians). In contrast, modern targeted therapies inhibit specific repair proteins like Poly(ADP-ribose) polymerase (PARP) or Ataxia telangiectasia and Rad3-related protein (ATR) to induce synthetic lethality, particularly in cancers with existing repair deficiencies (O'Connor, 2015, Molecular Cell). This system is fundamental to cell survival, and its dysregulation is a hallmark of cancer development and progression. Therapeutic modulation of these pathways aims to either induce catastrophic genomic instability in malignant cells or sensitize them to other DNA-damaging treatments (Pearl et al., 2015, Nature Reviews Cancer).

Other names

DNA damage responseDDRGenome maintenance systemDNA repair pathwaysDNA repair enzymes

Drugs targeting this system function through several distinct mechanisms: direct DNA damage via alkylation or cross-linking, inhibition of DNA-unwinding enzymes like topoisomerases, or the targeted inhibition of repair enzymes such as Poly(ADP-ribose) polymerase (PARP), Ataxia telangiectasia and Rad3-related protein (ATR), and Ataxia telangiectasia mutated (ATM) to prevent the correction of DNA lesions, ultimately triggering apoptosis (Lord & Ashworth, 2012, Nature; O'Connor, 2015, Molecular Cell).