Mechanisms Underlying Acrolein-Mediated Inhibition of Chromatin Assembly.
Acrolein is a major component of cigarette smoke and cooking fumes. Previously, we reported that acrolein compromises chromatin assembly; however, underlying mechanisms have not been defined. Here, we report that acrolein reacts with lysine residues, including lysines 5 and 12, sites important for chromatin assembly, on histone H4 in vitro and in vivo Acrolein-modified histones are resistant to acetylation, suggesting that the reduced H4K12 acetylation that occurs following acrolein exposure is probably due to the formation of acrolein-histone lysine adducts. Accordingly, the association of H3/H4 with the histone chaperone ASF1 and importin 4 is disrupted and the translocation of green fluorescent protein-tagged H3 is inhibited in cells exposed to acrolein. Interestingly, in vitro plasmid supercoiling assays revealed that treatment of either histones or ASF1 with acrolein has no effect on the formation of plasmid supercoiling, indicating that acrolein-protein adduct formation itself does not directly interfere with nucleosome assembly. Notably, exposure of histones to acrolein prior to histone acetylation leads to the inhibition of remodeling and spacing factor chromatin assembly, which requires acetylated histones for efficient assembly. These results suggest that acrolein compromises chromatin assembly by reacting with histone lysine residues at the sites critical for chromatin assembly and prevents these sites from physiological modifications.
Department of Environmental Medicine & Biochemistry and Molecular Pharmacology, New York University School of Medicine, Tuxedo, New York, USA.|Medical School of Nanjing University, Nanjing, China.
Lei
L
Fang
Department of Environmental Medicine & Biochemistry and Molecular Pharmacology, New York University School of Medicine, Tuxedo, New York, USA.
Danqi
D
Chen
Department of Physiology & Biophysics, University of California, Irvine, California, USA.
Clinton
C
Yu
Department of Environmental Medicine & Biochemistry and Molecular Pharmacology, New York University School of Medicine, Tuxedo, New York, USA.|Department of Pathology, SUNY Downstate Medical Center, New York, New York, USA.
Hongjie
H
Li
Department of Environmental Medicine & Biochemistry and Molecular Pharmacology, New York University School of Medicine, Tuxedo, New York, USA.
Jason
J
Brocato
Department of Physiology & Biophysics, University of California, Irvine, California, USA.
Lan
L
Huang
Department of Environmental Medicine & Biochemistry and Molecular Pharmacology, New York University School of Medicine, Tuxedo, New York, USA Chunyuan.jin@nyumc.org.
Chunyuan
C
Jin
D000107:Acetylation; D000171:Acrolein / Q000009:adverse effects*; D001665:Binding Sites / Q000187:drug effects; D002460:Cell Line; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects*; D006657:Histones / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism*; D013058:Mass Spectrometry; D026901:Membrane Transport Proteins / Q000378:metabolism
D006657:Histones; C545055:IPO4 protein, human; D026901:Membrane Transport Proteins; D000171:Acrolein; D008239:Lysine
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