title: Histone-catalyzed cleavage of nucleosomal DNA containing 2-deoxyribonolactone.
abstract: Oxidized abasic sites such as 2-deoxyribonolactone (L) are produced in DNA by a variety of oxidizing agents, including potent cytotoxic antitumor natural products. 2-Deoxyribonolactone is labile under alkaline conditions, but its half-life in free DNA at pH 7.5 is approximately 1 week. Independent generation of L at defined positions within nucleosomes reveals that the histone proteins catalyze strand scission and increase the rate between 11- and ∼43-fold. Mechanistic studies indicate that DNA-protein cross-links are not intermediates en route to strand scission and that C2 deprotonation is the rate-determining step. The use of mutant histone H4 proteins demonstrates that the lysine-rich tail that is often post-translationally modified in cells contributes to the cleavage of L but is not the sole source of the enhanced cleavage rates. Consideration of DNA repair in cells suggests that L formation in nucleosomal DNA as part of bistranded lesions by antitumor antibiotics results in de facto double strand breaks, the most deleterious form of DNA damage.
authors.affiliation: Department of Chemistry, Johns Hopkins University, 3400 North Charles Street, Baltimore, Maryland 21218, United States.
authors.forename: Chuanzheng
authors.initials: C
authors.lastname: Zhou
authors.forename: Marc M
authors.initials: MM
authors.lastname: Greenberg
mesh_terms: D001483:Base Sequence; D055162:Biocatalysis; D004247:DNA / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D053837:DNA Cleavage; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D007700:Kinetics; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D009707:Nucleosomes / Q000378:metabolism*; D011487:Protein Conformation; D013400:Sugar Acids
chemical_list: D006657:Histones; D009707:Nucleosomes; D013400:Sugar Acids; C056405:2,4,5-trihydroxypentanoic acid gamma-lactone; D004247:DNA