title: 4-Hydroxynonenal oxidatively modifies histones: implications for Alzheimer's disease.
abstract: There is increasing evidence of DNA oxidation and altered DNA repair mechanisms in Alzheimer's disease (AD) brain. Histones, which interact with DNA, conceivably could provide a protective shield for DNA against oxidative stress. However, because of their abundant lysine residues, histones may be a target for 4-hydroxynonenal (HNE) modification. In this study, we have shown that HNE binds to histones and that this binding affects the conformation of the histone, measured by electron paramagnetic resonance in conjunction with a protein-specific spin label. The covalent modification to the histone by HNE affects the ability of the histone to bind DNA. Interestingly, acetylated histones appear to be more susceptible to HNE modifications than control histones. Conceivably, altered DNA-histone interactions, subsequent to oxidative modification of histones by the lipid peroxidation product HNE, may contribute to the vulnerability of DNA to oxidation in AD brain.
authors.affiliation: Department of Chemistry, University of Kentucky, Lexington, KY 40506, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Drake
authors.forename: Robin
authors.initials: R
authors.lastname: Petroze
authors.forename: Alessandra
authors.initials: A
authors.lastname: Castegna
authors.forename: Qunxing
authors.initials: Q
authors.lastname: Ding
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Keller
authors.forename: William R
authors.initials: WR
authors.lastname: Markesbery
authors.forename: Mark A
authors.initials: MA
authors.lastname: Lovell
authors.forename: D Allan
authors.initials: DA
authors.lastname: Butterfield
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000447:Aldehydes / Q000378:metabolism*; D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D002417:Cattle; D003497:Cyclic N-Oxides / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004578:Electron Spin Resonance Spectroscopy / Q000379:methods; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D011485:Protein Binding; D011487:Protein Conformation; D012965:Sodium Chloride / Q000494:pharmacology; D013950:Thymus Gland; D013997:Time Factors
chemical_list: D000447:Aldehydes; D003497:Cyclic N-Oxides; D015853:Cysteine Proteinase Inhibitors; D006657:Histones; C017480:4-maleimido-2,2,6,6-tetramethylpiperidinooxyl; D012965:Sodium Chloride; D004247:DNA; C027576:4-hydroxy-2-nonenal