Cellular DNA and histone cysteine residues

Cellular DNA and histone cysteine residues represent a composite molecular target for several potent chemotherapeutic and alkylating agents. Cellular DNA, specifically the nucleophilic sites such as the N-7 position of guanine, is a primary target for alkylation, which leads to interstrand and intrastrand crosslinking that inhibits replication and transcription. Histone proteins, particularly the cysteine residues (such as Cys110 in Histone H3), serve as additional nucleophilic targets that can form covalent adducts or DNA-protein crosslinks when exposed to bifunctional electrophiles. The interaction with these targets disrupts chromatin structure and genomic integrity, ultimately triggering signal transduction pathways that lead to cell cycle arrest and apoptosis. This mechanism is central to the therapeutic efficacy of drugs like busulfan in treating chronic myeloid leukemia and arsenic trioxide in acute promyelocytic leukemia.

Other names

DNA and histone thiolsGenomic DNA and histone cysteine residuesNuclear DNA and histone sulfhydryl groups

Alkylating agents like busulfan form covalent bonds with the N-7 position of guanine in cellular DNA and react with the sulfhydryl groups of cysteine residues in histone proteins, leading to DNA-protein crosslinks, DNA fragmentation, and apoptosis. Arsenic trioxide similarly targets cysteine-rich proteins and induces DNA damage to trigger programmed cell death in malignant cells.