DNA crosslink (ICL)

DNA crosslinks are covalent linkages formed between two nucleotide bases, either within a single DNA strand (intrastrand) or between the two opposing strands of the double helix (interstrand crosslinks, ICLs). These lesions represent one of the most severe forms of DNA damage because they physically obstruct the separation of DNA strands, which is essential for fundamental cellular processes such as DNA replication and transcription (Noll et al., 2006, Chemical Reviews). In clinical oncology, the induction of DNA crosslinks is a validated therapeutic strategy utilized by several classes of cytotoxic drugs, including platinum-based agents like cisplatin and alkylating agents like cyclophosphamide (Dasari & Tchounwou, 2014, European Journal of Pharmacology). These agents are particularly effective against rapidly proliferating malignant cells, which are more susceptible to replication fork collapse and subsequent apoptosis triggered by unrepaired crosslinks. However, the therapeutic index is often limited by the cell's endogenous repair mechanisms, such as the Fanconi anemia (FA) pathway and nucleotide excision repair (NER), which can lead to drug resistance (Deans & West, 2011, Nature Reviews Cancer). Furthermore, because these drugs also damage DNA in healthy cells, they are associated with significant systemic toxicities, including myelosuppression and the potential for developing secondary cancers due to their inherent mutagenic properties (NIH, National Cancer Institute).

Other names

DNA interstrand crosslinkDNA intrastrand crosslinkDNA adductInterstrand DNA crosslinkIntrastrand DNA crosslink

Induction of covalent bonds between DNA bases on the same or opposite strands, physically preventing the DNA double helix from unwinding and thereby blocking replication and transcription machinery (Dasari & Tchounwou, 2014, European Journal of Pharmacology).