4-Hydroxynonenal oxidatively modifies histones: Implications for Alzheimer's disease

Jennifer Drake; Robin Petroze; Alessandra Castegna; Qunxing Ding; Jeffrey N. Keller; William R. Markesbery; Mark A. Lovell; D. Allan Butterfield

doi:10.1016/j.neulet.2003.11.047

4-Hydroxynonenal oxidatively modifies histones: Implications for Alzheimer's disease

Jennifer Drake, Robin Petroze, Alessandra Castegna, Qunxing Ding, Jeffrey N. Keller, William R. Markesbery, Mark A. Lovell, D. Allan Butterfield

Research output: Contribution to journal › Article › peer-review

68 Scopus citations

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.

Original language	English
Pages (from-to)	155-158
Number of pages	4
Journal	Neuroscience Letters
Volume	356
Issue number	3
DOIs	https://doi.org/10.1016/j.neulet.2003.11.047
State	Published - Feb 19 2004

Bibliographical note

Funding Information:
This research was supported in part by NIH grants AG05119 and AG10836 to DAB, NIH grant 5P50AG05114 and a grant from the Abercombie Foundation to WRM, and NIH grants AG018437 and AG05119 and an American Heart Association grant to JNK.

Keywords

Alzheimer's disease
DNA oxidation
Histone-DNA interactions
Protein conformation
Spin labeling

ASJC Scopus subject areas

General Neuroscience

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10.1016/j.neulet.2003.11.047

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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.",

keywords = "Alzheimer's disease, DNA oxidation, Histone-DNA interactions, Protein conformation, Spin labeling",

author = "Jennifer Drake and Robin Petroze and Alessandra Castegna and Qunxing Ding and Keller, {Jeffrey N.} and Markesbery, {William R.} and Lovell, {Mark A.} and Butterfield, {D. Allan}",

note = "Funding Information: This research was supported in part by NIH grants AG05119 and AG10836 to DAB, NIH grant 5P50AG05114 and a grant from the Abercombie Foundation to WRM, and NIH grants AG018437 and AG05119 and an American Heart Association grant to JNK.",

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AU - Ding, Qunxing

AU - Keller, Jeffrey N.

AU - Markesbery, William R.

AU - Lovell, Mark A.

AU - Butterfield, D. Allan

N1 - Funding Information: This research was supported in part by NIH grants AG05119 and AG10836 to DAB, NIH grant 5P50AG05114 and a grant from the Abercombie Foundation to WRM, and NIH grants AG018437 and AG05119 and an American Heart Association grant to JNK.

PY - 2004/2/19

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N2 - 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.

AB - 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.

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KW - Protein conformation

KW - Spin labeling

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4-Hydroxynonenal oxidatively modifies histones: Implications for Alzheimer's disease

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ASJC Scopus subject areas

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