DNA cross-link (ICL) (ICL)

DNA cross-links are covalent chemical bonds that form between two nucleotides in a DNA molecule, occurring either on the same strand (intrastand) or between opposing strands (interstrand cross-links or ICLs) (Source: PubMed PMC3100973). These lesions are highly cytotoxic because they prevent the DNA double helix from unwinding, thereby stalling essential cellular processes such as DNA replication and transcription (Source: Nature Reviews Molecular Cell Biology). In clinical oncology, DNA cross-linking is a validated therapeutic strategy; several classes of chemotherapy, including platinum-based agents and nitrogen mustards, exert their anti-tumor effects by inducing these lesions (Source: StatPearls). The resulting DNA damage triggers cell cycle arrest and apoptosis, particularly in rapidly proliferating malignant cells (Source: NCI Drug Dictionary). However, the efficacy of these drugs is often limited by cellular DNA repair mechanisms, such as the Fanconi anemia pathway and nucleotide excision repair, which can remove the cross-links and lead to chemoresistance (Source: Nature Reviews Cancer). Furthermore, because these agents are not site-specific, they can cause significant systemic toxicity and increase the risk of secondary cancers (Source: PubMed PMC4113511).

Other names

Interstrand cross-linkIntrastand cross-linkDNA-DNA crosslinkDNA adductDNA lesion

Induction of covalent linkages between DNA strands (interstrand) or within a single strand (intrastand), which physically prevents the separation of the DNA double helix, thereby blocking replication and transcription and inducing apoptosis (Source: StatPearls, PubMed PMC3100973).