4-Hydroxynonenal oxidatively modifies histones: implications for Alzheimer's disease.
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.
Drake
Jennifer
J
Department of Chemistry, University of Kentucky, Lexington, KY 40506, USA.
Petroze
Robin
R
Castegna
Alessandra
A
Ding
Qunxing
Q
Keller
Jeffrey N
JN
Markesbery
William R
WR
Lovell
Mark A
MA
Butterfield
D Allan
DA
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
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