DNA crosslinking and DNA damage induction by platinum agent

This entry does **not** refer to a single molecular target such as a receptor or enzyme but rather describes a **mechanism**—the process by which platinum-based chemotherapeutic agents exert their cytotoxic effects on cells. Platinum compounds like cisplatin bind covalently to nucleophilic sites on purine bases within nuclear DNA. This results primarily in the formation of intra-strand crosslinks between adjacent guanines or guanine–adenine pairs (>90% of lesions), as well as less frequent interstrand links that physically tether complementary strands together. These structural changes disrupt normal base pairing and helical geometry, blocking essential processes such as replication and transcription. If unrepaired by cellular mechanisms—primarily nucleotide excision repair—the accumulation of these lesions leads to activation of cell cycle checkpoints followed by apoptosis. Some platinum drugs also generate bulky ternary complexes involving both proteins bound at damaged sites (“DNA-protein crosslinks”), which further impede polymerase activity and complicate lesion removal[4]. The effectiveness—and resistance—to this class depends heavily on the tumor’s ability to recognize/repair such damage; thus genes like ERCC1/BRCA1 serve as important clinical biomarkers predicting response. Because “DNA crosslinking/DNA damage induction by platinum agent” is not itself a discrete molecular entity but rather an effect/process induced pharmacologically within cells using specific drugs targeting nucleic acids directly—not via binding protein targets—it should not be considered a canonical therapeutic target per se.[6]

Other names

Platinum-induced DNA crosslinkingPlatinum–DNA adductsCisplatin-DNA adductsPlatinum-based DNA damage

Platinum agents form covalent bonds with the N7 position of purine bases in DNA, leading to the formation of various types of platinum–DNA adducts. The most common are 1,2-intrastrand crosslinks (>90%), but interstrand crosslinks and monoadducts also occur. These lesions distort the double helix structure, block replication and transcription machinery, induce double-strand breaks if not repaired properly, and ultimately trigger cell death via apoptosis when repair is insufficient or overwhelmed[1][2][3]. Additionally, platinum drugs can induce bulky ternary complexes involving both DNA and proteins (DNA-protein crosslinks), which further inhibit essential cellular processes[4].