DNA Crosslinking (Cisplatin)

DNA crosslinking by cisplatin refers to the formation of covalent bonds between DNA bases, primarily induced by the chemotherapeutic agent cisplatin (cis-diamminedichloroplatinum(II)). This process disrupts normal DNA function and is central to cisplatin’s cytotoxic effects against cancer cells. Cisplatin enters cells and undergoes aquation, replacing its chloride ligands with water molecules. The resulting activated complex reacts with nucleophilic sites on DNA, especially at the N7 position of guanine bases. The majority of cisplatin-induced crosslinks are intrastrand, occurring between adjacent purine bases such as 1,2-GG or 1,2-AG sequences. A smaller proportion forms interstrand crosslinks or monofunctional adducts. In addition to direct DNA-DNA crosslinks, cisplatin can also induce ternary complexes involving both DNA and proteins (DNA–protein cross-links), which are more persistent and inhibit cellular repair mechanisms more effectively than simple intrastrand adducts. These lesions distort the helical structure of DNA, block replication and transcription processes, arrest cell cycle progression at S/G1/G2-M phases, and ultimately trigger apoptosis in rapidly dividing cancer cells. Cisplatin-induced bulky adducts are recognized by cellular damage response pathways. Repair is attempted mainly via nucleotide excision repair (NER) mechanisms; however, some lesions—especially interstrand or protein-linked—are difficult for cells to remove efficiently. Cisplatin’s ability to form stable intra/interstrand crosslinks underpins its effectiveness against a wide range of cancers including ovarian, lung, head/neck cancers as well as testicular and bladder tumors. Recent studies show that it can eradicate bacterial persister cells through growth-independent killing mediated by intra-strand crosslinking.

Other names

Cisplatin-induced DNA damageCisplatin DNA adductsPlatinum DNA crosslinks

Cisplatin enters cells and forms DNA adducts, primarily intrastrand crosslinks between guanine bases, disrupting DNA replication and transcription, leading to cell cycle arrest and apoptosis.