title: Ni(II) affects ubiquitination of core histones H2B and H2A.
abstract: The molecular mechanisms of nickel-induced malignant cell transformation include effects altering the structure and covalent modifications of core histones. Previously, we found that exposure of cells to Ni(II) resulted in truncation of histones H2A and H2B and thus elimination of some modification sites. Here, we investigated the effect of Ni(II) on one such modification, ubiquitination, of histones H2B and H2A in nuclei of cultured 1HAEo- and HPL1D human lung cells. After 1-5 days of exposure, Ni(II) up to 0.25 mM stimulated mono-ubiquitination of both histones, while at higher concentrations a suppression was found. Di-ubiquitination of H2A was not affected except for a drop after 5 days at 0.5 mM Ni(II). The decrease in mono-ubiquitination coincided with the appearance of truncated H2B that lacks the K120 ubiquitination site. However, prevention of truncation did not avert the decrease of H2B ubiquitination, indicating mechanistic independence of these effects. The changes in H2B ubiquitination did not fully coincide with concurrent changes in the nuclear levels of the ubiquitin-conjugating enzymes Rad6 and UbcH6. Overall, our results suggest that dysregulation of H2B ubiquitination is a part of Ni(II) adverse effects on gene expression and DNA repair which may assist in cell transformation.
authors.affiliation: Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Frederick, MD 21702-1201, USA.
authors.forename: Aldona A
authors.initials: AA
authors.lastname: Karaczyn
authors.forename: Filip
authors.initials: F
authors.lastname: Golebiowski
authors.forename: Kazimierz S
authors.initials: KS
authors.lastname: Kasprzak
mesh_terms: D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000166:cytology; D008745:Methylation / Q000187:drug effects; D009532:Nickel / Q000633:toxicity*; D025801:Ubiquitin / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism
chemical_list: D006657:Histones; D025801:Ubiquitin; D009532:Nickel; C489963:UBE2E1 protein, human; D044763:Ubiquitin-Conjugating Enzymes