Cisplatin-DNA adduct (Pt-DNA adduct)

DNA modified by cisplatin refers to the genomic DNA that has undergone covalent modification by the platinum-based chemotherapeutic agent cisplatin. The primary interaction involves the formation of platinum-DNA adducts, most commonly 1,2-intrastrand d(GpG) and d(ApG) crosslinks, which significantly bend and unwind the DNA double helix (Jamieson & Lippard, 1999). These structural distortions act as physical barriers to DNA polymerases and RNA polymerases, thereby halting DNA replication and gene transcription (StatPearls, 2023). The cellular recognition of these adducts by damage-sensing proteins initiates signaling cascades, such as the p53 pathway, leading to cell cycle arrest and programmed cell death (Galluzzi et al., 2012). While highly effective in treating various solid tumors, the efficacy of cisplatin is often limited by the cell's ability to repair these adducts through the nucleotide excision repair (NER) pathway (PubMed, PMID: 22437870). This target is central to the treatment of testicular, ovarian, and lung cancers, though its formation is also associated with significant systemic toxicities like kidney damage and hearing loss (NIH, 2023).

Other names

Cisplatin-modified DNAPlatinum-DNA crosslinksIntrastrand DNA crosslinksInterstrand DNA crosslinksPt-DNA lesionscis-Diamminedichloroplatinum(II)-DNA complex

Cisplatin enters the cell and undergoes aquation to become a reactive electrophilic species that binds to the N7 position of purine bases, primarily guanine. This results in the formation of 1,2-intrastrand crosslinks (approximately 90% of adducts), 1,3-intrastrand crosslinks, and interstrand crosslinks (StatPearls, 2023). These adducts cause a significant bend in the DNA helix, which inhibits the progression of DNA and RNA polymerases, effectively blocking replication and transcription (Dasari & Bernard Tchounwou, 2014).