Genomic deoxyribonucleic acid (DNA) intra-strand crosslinks (DNA)

Genomic DNA serves as a primary therapeutic target for several classes of antineoplastic agents, most notably platinum-based compounds. Intra-strand crosslinks are covalent adducts formed when a drug molecule binds to two nucleotide bases on the same strand of the DNA helix, typically at the N7 position of adjacent guanine residues, forming d(GpG) or d(ApG) lesions (Dasari & Tchounwou, 2014). These lesions cause significant conformational changes in the DNA structure, which physically impede the progression of replication and transcription machinery (Wang & Lippard, 2005). The resulting stalled replication forks and inhibited gene expression trigger cellular stress responses, leading to cell cycle arrest and the induction of apoptosis via the intrinsic pathway (Siddik, 2003). While these crosslinks are highly effective at killing rapidly dividing cancer cells, their formation is not site-specific, leading to damage in healthy tissues and associated systemic toxicities such as nephrotoxicity and neurotoxicity. The clinical efficacy of targeting DNA in this manner is often modulated by the cell's DNA repair capacity, particularly the nucleotide excision repair (NER) pathway, which can remove these adducts and contribute to drug resistance (Jung & Lippard, 2007).

Other names

DNA intra-strand adductsIntrastrand DNA cross-linksPlatinum-DNA adductsGenomic DNA adductsd(GpG) intra-strand crosslinks

Formation of covalent intra-strand adducts, primarily at the N7 position of adjacent purine bases (mostly guanine), which distorts the DNA helix and physically obstructs replication and transcription machinery (Dasari & Tchounwou, 2014; Wang & Lippard, 2005).