Deoxyribonucleic acid (DNA) and DNA-processing enzymes (DNA and DNA-processing enzymes)

Deoxyribonucleic acid (DNA) is the molecule that carries genetic instructions for the development, functioning, growth, and reproduction of all known organisms and many viruses (NHGRI, 2023). DNA-processing enzymes, such as DNA polymerases, topoisomerases, helicases, and ligases, are critical for the replication, repair, and transcription of the genome (Alberts et al., 2014). In oncology, DNA is a primary target for various chemotherapeutic agents that induce structural damage or cross-linking, while associated enzymes are targeted to prevent the repair of such damage or to stall replication forks (StatPearls, 2023). For instance, topoisomerase inhibitors prevent the re-ligation of DNA strands, leading to lethal double-strand breaks, and PARP inhibitors block essential repair pathways in cells with existing genetic deficiencies (Nature Reviews Cancer, 2021). Beyond cancer, DNA-processing enzymes in bacteria and viruses are targeted by antibiotics and antivirals to inhibit pathogen replication (PubMed, 2022). However, because DNA maintenance is universal to all human cells, drugs targeting these pathways often exhibit narrow therapeutic windows and significant systemic toxicities (StatPearls, 2023).

Other names

Genetic materialDNA replication machineryDNA repair enzymesDNA-modifying enzymesGenome maintenance machinery

Drugs targeting DNA and its associated enzymes act through several mechanisms: alkylating agents (e.g., cisplatin) create covalent cross-links that impede replication; antimetabolites (e.g., 5-fluorouracil) inhibit the synthesis of nucleotide precursors; topoisomerase inhibitors (e.g., etoposide, irinotecan) stabilize DNA-enzyme cleavage complexes to induce strand breaks; and PARP inhibitors (e.g., olaparib) prevent the repair of single-strand breaks, leading to synthetic lethality in BRCA-deficient cells (StatPearls, 2023; Nature Reviews Cancer, 2021).