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Ni(ll) Specifically Cleaves the C-Terminal Tail of the Major Variant of Histone H2A and Forms an Oxidative Damage-Mediating Complex with the Cleaved-Off Octapeptide

Published

Author(s)

W Bal, R Liang, J Lukszo, S Lee, M. Dizdaroglu, K S. Kasprzak

Abstract

The Acetyl-TESHHK-amide peptide, modeling a part of the C-terminal tailof histone H2A, was found previously by us to undergo at pH 7.4 a Ni(II)-assisted hydrolysis of the E-S peptide bond with formation of a stronger Ni(II) complex with the SHHK-amide product [Bal, W., et al., (1998)Chem. Res. Toxicol. 11, 1014-1023]. To further characterize the hydrolysis and test the resulting Ni(II) complex for redox activity, bovine H2A and three peptides, Acetyl-LLGKVTIAQGGVLPNIQAVLLPKKTESHHKAKGK (H2A34), modeling the entire C-tailof H2A; SHHKAKGK (H2A8), modeling the cut-off product of hydrolysis; and Acetyl-KTESHKAKGK (H2A10), modeling a putative Ni(II) binding site in a minor variant H2A.1 of human histone H2A, were investigated. The Ni(II)-assisted hydrolysis of H2A and H2A34 was found to proceed approximately seven- fold faster than that of the Ni(II)-AcetylTESHHKamide complex under comparable conditions. In both cases, Ni(II) complex with H2A8 appeared to be the smaller product of the hydrolysis, indicating a high site specificity of the reaction. Of three other metals tested with H2A34, only Cu(II) cleaved the E-S bond, although much less efficiently than Ni(II); Co(II) and Zn(II) had no effect whatsoever. The H2A10 complex with Ni(II) appeared to be fully resistant to hydrolytic cleavage and did not show any redox activity with H2O2 at pH 7.4. Likewise redox-inactive was Ni(II)-H2A34 complex. In contrast, the Ni(II)-H2A8 complex promoted oxidative damage of pUC19 DNA by H2O2, evidenced by a significant increase of single strand breaks and nucleobase modifications typical for a hydroxyl radical-like species attack on DNA. Interestingly, instead of 8-oxopurines, the corresponding formamidopyrimidines were the major products of the damage. The difference in redox activity between Ni(II)-H2A34 and Ni(II)-H2A8 is most likely associated with their different geometries: octahedral and square planar, respectively. Incubation of Ni(II)-H2A8 with H2O2 also resulted in degradation of the peptide ligand, especially at its Ser and His residues. Thus, binding of Ni(II) to the -ESHHK- motif of histone H2A C-tail is damaging to the histone C-terminal tail and to histone associated DNA. The results support a dual mechanism of Ni(II)-induced carcinogenesis, including both genotoxic and epigenetic effects.
Citation
Chemical Research in Toxicology
Volume
13
Issue
No. 7

Keywords

4, 6-Diamino-5-formamidopyrimidine, 8-Hydrozyguanine, Histone H2A, Ni-induced Carcinogenesis, Oxidative DNA damage

Citation

Bal, W. , Liang, R. , Lukszo, J. , Lee, S. , Dizdaroglu, M. and Kasprzak, K. (2000), Ni(ll) Specifically Cleaves the C-Terminal Tail of the Major Variant of Histone H2A and Forms an Oxidative Damage-Mediating Complex with the Cleaved-Off Octapeptide, Chemical Research in Toxicology (Accessed April 12, 2024)
Created July 1, 2000, Updated February 17, 2017