DNA intrastrand cross-links

DNA intrastrand cross-links are covalent chemical modifications formed between two adjacent or nearby nucleotides on the same strand of a DNA molecule (Wikipedia, 2024). These lesions are the primary mechanism of action for platinum-based chemotherapeutic agents, such as cisplatin and carboplatin, which predominantly target adjacent guanine (GpG) or adenine-guanine (ApG) sequences (NIH, 2016). The formation of these adducts causes significant structural distortion and kinking of the DNA double helix, which physically blocks the progression of DNA and RNA polymerases (ACS, 2010). This interference inhibits essential cellular processes, including DNA replication and transcription, ultimately triggering apoptotic cell death in rapidly dividing cancer cells (PubMed, 2001). While highly effective in treating various malignancies, the persistence and repair of these cross-links, primarily via the nucleotide excision repair pathway, are critical determinants of drug sensitivity and the development of chemoresistance (Frontiers, 2024). The clinical utility of targeting DNA through intrastrand cross-linking is well-established in the treatment of solid tumors, including ovarian, testicular, and lung cancers (NIH, 2024). However, the non-specific nature of DNA damage leads to significant side effects, such as nephrotoxicity and neurotoxicity, which remain major therapeutic challenges (PubMed, 2006).

Other names

DNA intrastrand adductsPt-DNA adducts1,2-intrastrand d(GpG) adducts1,2-intrastrand d(ApG) adductsIntrastrand DNA lesions

Formation of covalent intrastrand cross-links between adjacent purine bases in DNA, causing structural distortion that inhibits replication and transcription.