DNA intrastrand crosslink sites (DNA intrastrand sites)

DNA intrastrand sites are specific locations on a single strand of DNA where covalent bonds are formed between adjacent or nearby nucleotides by exogenous agents, most notably platinum-based chemotherapeutic drugs like cisplatin (PubChem, CID 5702198). These intrastrand crosslinks, which account for approximately 90% of DNA lesions caused by such drugs, typically occur at 1,2-d(GpG) or 1,2-d(ApG) sequences (Nature Reviews Cancer, 2007, 7:573-584). The resulting adducts induce a sharp bend in the DNA helix, which serves as a physical barrier to DNA and RNA polymerases, thereby inhibiting DNA replication and gene transcription (PubMed, PMID: 17646865). This disruption of genomic integrity and function triggers signaling cascades that lead to cell cycle arrest and apoptosis, making these sites a critical target in the treatment of various malignancies, including testicular, ovarian, and lung cancers (NIH/NCI Dictionary). However, the efficacy of targeting these sites can be limited by cellular DNA repair mechanisms, such as nucleotide excision repair (NER), which can remove the adducts and lead to drug resistance (StatPearls, NBK547695).

Other names

DNA intrastrand adductsIntrastrand DNA crosslinksPt-DNA adducts1,2-intrastrand d(GpG) crosslinks1,2-intrastrand d(ApG) crosslinks

Platinum-based drugs bind covalently to the N7 position of purine bases (primarily guanine) on a single DNA strand to form 1,2-intrastrand crosslinks (PubChem, CID 5702198). These adducts distort the DNA structure, inhibiting replication and transcription, and triggering apoptosis (Nature Reviews Cancer, 2007, 7:573-584).