Mechanisms Underlying Acrolein-Mediated Inhibition of Chromatin Assembly

Abstract

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.

Nucleosome Histone Tail Conformation and Dynamics: Impacts of Lysine Acetylation and a Nearby Minor Groove Benzo[a]pyrene-Derived Lesion

“…89, 90 Greenberg and coworkers have shown that DNA abasic lesions react with tail lysine residues to form cross-links whose rates of formation depend on the translational setting of the lesion in the nucleosome; furthermore, they have suggested that such cross-links would impede histone tail post-translational modifications. 91, 92 Additionally, it has recently been shown for histone H2B in vivo , that the suspected human carcinogen furan can produce a cross-link adduct with a non-tail lysine residue that is crucial for nucleosome stability and a target for PTMs; impaired PTM and subsequent alterations in gene expression could result.…”

The effects of acetaldehyde exposure on histone modifications and chromatin structure in human lung bronchial epithelial cells

“…The illustrated decrease in histone acetylation level could result from aldehyde-histone adduct formation or reduced expression and/or activity of histone acetyltransferases following aldehyde exposure. The activity and expression of HAT1, a histone acetyltransferase specific for H4K12 acetylation, were not changed by acrolein treatment (Chen et al 2013; Fang et al 2016). Thus, it seems fair to assume that acrolein-induced reduction of histone acetylation is triggered by the formation of acrolein histone lysine adducts.…”

Histone variants in environmental-stress-induced DNA damage repair

“…We have demonstrated that the potential carcinogen acrolein, which is abundant in cigarette smoke and cooking fumes, reacts with lysines 5 and 12 on cytosolic histone H4 in vitro and in cells, preventing these sites from being physiologically acetylated by histone acetyltransferases including HAT1 [71,72]. Reduction of H4K5&12ac and/or other histone modifications following acrolein exposure disrupted the association of H3-H4 with importin 4 as well as Asf1, leading to inhibition of histone nuclear import and assembly into chromatin [81,82]. To examine if this could be a common characteristic of other type of aldehydes, we further investigated how established carcinogen formaldehyde, a simplest aldehyde, regulates histone modifications and chromatin assembly.…”