DNA crosslinking by alkylation

DNA crosslinking by alkylation is not a single molecular target but rather describes the chemical process where certain agents—primarily alkylating agents—form covalent bonds between two nucleotide residues within the same strand (intrastrand) or across both strands (interstrand) of double-stranded DNA. This process can also involve covalent links between DNA and proteins. Alkylating agents transfer an alkyl group onto electron-rich atoms in nucleotide bases such as guanine, adenine, cytosine, or thymidine. The resulting crosslinks disrupt essential cellular processes like replication and transcription by physically blocking strand separation or template reading. If unrepaired, these lesions trigger cell cycle arrest and apoptosis. This mechanism underlies the cytotoxicity of several major classes of anticancer drugs—including nitrogen mustards, platinum-based compounds like cisplatin/carboplatin/oxaliplatin, mitomycin C, psoralens activated by UV light, and aziridinylquinones—which are used clinically for treating leukemia and solid tumors. While highly effective against rapidly dividing cancer cells due to their inability to repair extensive damage efficiently, these drugs also pose significant risks for normal tissues with high turnover rates. Because "DNA crosslinking by alkylation" refers broadly to a class of chemical modifications rather than a discrete gene product or protein receptor/enzyme/transporter/etc., it is not considered a canonical therapeutic target in the conventional sense but rather describes an important mechanistic endpoint exploited pharmacologically.

Other names

DNA alkylation and crosslinkingDNA interstrand cross-linkingDNA ICL formationDNA-protein crosslinking

Covalent binding to nucleophilic sites on DNA bases via alkyl group transfer, leading to intra/interstrand or DNA-protein crosslinks that block replication and transcription