Genomic DNA cross-links (DNA ICLs)

Genomic DNA cross-links are covalent chemical bonds formed between the two strands of the DNA double helix (interstrand cross-links, ICLs) or within a single strand (intrastrand cross-links). These lesions represent one of the most severe forms of DNA damage because they physically obstruct the separation of DNA strands, thereby blocking essential cellular processes such as DNA replication and transcription (Clauson et al., 2013, Cold Spring Harb Perspect Biol). In clinical oncology, inducing DNA cross-links is a primary mechanism for several classes of chemotherapeutic agents, including platinum-based compounds like cisplatin and alkylating agents like mitomycin C. These drugs target the high proliferative rate of cancer cells, where the persistence of unrepaired cross-links leads to replication fork collapse, double-strand breaks, and subsequent programmed cell death (Deans & West, 2011, Nat Rev Cancer). The repair of these lesions requires the coordinated action of multiple pathways, including the Fanconi anemia (FA) pathway, nucleotide excision repair (NER), and homologous recombination (HR) (Kottemann & Smogorzewska, 2013, Nature). While effective against cancer, the formation of DNA cross-links in healthy cells can lead to significant side effects, including myelosuppression and the risk of secondary malignancies due to the mutagenic nature of the damage (Noll et al., 2006, Chem Rev).

Other names

DNA interstrand cross-linksDNA intrastrand cross-linksDNA adductsCovalent DNA bridges

Induction of covalent bonds between or within DNA strands to inhibit replication and transcription, leading to cell death (Deans & West, 2011, Nat Rev Cancer).