DNA 1,2-intrastrand crosslink sites (DNA 1,2-intrastrand crosslinks)

DNA 1,2-intrastrand crosslink sites are the primary molecular lesions formed by platinum-based chemotherapeutic agents such as cisplatin, carboplatin, and oxaliplatin (PMID: 17406218). These crosslinks occur when the platinum compound binds covalently to the N7 positions of two adjacent purine bases, most commonly two guanines (1,2-d(GpG)) or an adenine and a guanine (1,2-d(ApG)), on the same strand of DNA (PMID: 11441244). The formation of these adducts induces a sharp bend of approximately 30-90 degrees in the DNA helix and unwinds the duplex, which physically obstructs the progression of DNA and RNA polymerases (PMID: 24511367). This structural distortion is recognized by high-mobility group (HMG) domain proteins and other damage-recognition factors, which can shield the adducts from repair or initiate signaling cascades. If the damage is not successfully removed by the nucleotide excision repair (NER) pathway, it triggers cell cycle arrest and programmed cell death (apoptosis). In clinical oncology, these crosslink sites are the critical targets for treating various malignancies, including testicular, ovarian, and non-small cell lung cancers, although their efficacy can be limited by the upregulation of DNA repair mechanisms (PMID: 17406218).

Other names

1,2-intrastrand d(GpG) crosslinks1,2-intrastrand d(ApG) crosslinksCisplatin-DNA adductsDNA 1,2-intrastrand adductsPlatinum-DNA adducts

Platinum-based drugs bind covalently to the N7 positions of purine bases to form 1,2-intrastrand crosslinks (PMID: 17406218). These adducts cause significant bending and unwinding of the DNA double helix, which physically obstructs DNA polymerase and RNA polymerase (PMID: 24511367). This inhibition of replication and transcription triggers DNA damage response pathways, ultimately leading to cell cycle arrest and apoptosis.