DNA crosslinking via platinum adduct formation

DNA crosslinking via platinum adduct formation refers to the process by which platinum-based anticancer drugs—most notably cisplatin, carboplatin, and oxaliplatin—form covalent bonds with nucleophilic sites on the purine bases within cellular DNA. This results in several types of lesions: Intrastrand Crosslinks: The most common lesion where two adjacent guanines or an adenine and guanine on the same strand are linked by a bifunctional platinum complex. These distort the helical structure. Interstrand Crosslinks: Less frequent but highly cytotoxic; these link complementary strands together at GC-rich regions, blocking separation required for replication and transcription. DNA-protein Crosslinks: Ternary complexes involving both protein(s) and platinated DNA can also form[1][4]. The biological consequence is profound disruption of essential cellular processes such as replication and transcription. Cells recognize these bulky lesions as severe damage, activating nucleotide excision repair (NER) pathways for intrastrand links or coordinated NER/homologous recombination for interstrand links. If repair fails or is overwhelmed—as often occurs in cancer cells with defective repair machinery—the result is apoptosis. This mechanism underlies the clinical efficacy of platinum drugs against various cancers but also contributes to resistance when tumor cells upregulate relevant repair proteins like ERCC1 or BRCA1[3]. The process itself is not a molecular target like an enzyme or receptor but rather describes a class of drug-induced chemical modifications central to chemotherapy's mode-of-action. Because \"DNA crosslinking via platinum adduct formation\" does not refer to a discrete molecular entity such as a protein target but rather describes a chemical event/process induced by certain drugs on genomic material, it should not be considered a canonical therapeutic target per se. It represents an important pharmacological effect exploited in cancer therapy rather than being itself \"druggable\" in conventional terms[1][2][3].

Other names

Platinum-DNA adductsPlatinum-induced DNA crosslinksPt-DNA adductsCisplatin-DNA crosslinksPlatinum drug–DNA lesions

Formation of covalent platinum-DNA adducts leading to intra-strand and inter-strand crosslinks that distort the double helix, block replication/transcription, and trigger apoptosis[1][3][5].