DNA interstrand crosslink (ICL) (ICL)

DNA interstrand crosslinks (ICLs) are highly toxic DNA lesions formed when bifunctional agents covalently link two nucleotides on opposite strands of the DNA double helix (Source: Nature Reviews Molecular Cell Biology, PMID: 23426330). These lesions are a primary target for several classes of chemotherapeutic agents, including platinum-based drugs like cisplatin and alkylating agents like mitomycin C (Source: PubChem, CID 5702198). By physically tethering the two strands together, ICLs prevent the strand separation necessary for essential cellular processes such as DNA replication and transcription (Source: NIH National Cancer Institute). If left unrepaired, these crosslinks lead to the collapse of replication forks and the formation of double-strand breaks, ultimately triggering programmed cell death or apoptosis (Source: Molecular Cell, PMID: 20920695). The repair of ICLs is a complex process involving the Fanconi anemia (FA) pathway, nucleotide excision repair, and homologous recombination (Source: StatPearls, NBK545156). Because cancer cells often exhibit high rates of proliferation, they are particularly sensitive to ICL-inducing agents, although systemic toxicities such as nephrotoxicity and myelosuppression remain significant clinical challenges (Source: Mayo Clinic). Resistance to these agents often arises through the upregulation of DNA repair pathways or increased drug efflux.

Other names

DNA-DNA crosslinksDNA cross-linksInterstrand DNA crosslinksIntrastrand DNA crosslinksDNA adductsDNA / DNA crosslink sites

Bifunctional alkylating or platinating agents form covalent bonds between two nucleotide bases on opposite strands (interstrand) or the same strand (intrastrand), preventing strand separation and blocking replication/transcription (Source: NIH National Cancer Institute).