The octapeptidic end of the C-terminal tail of histone H2A is cleaved off in cells exposed to carcinogenic nickel(II).
We have demonstrated previously that Ni(II) binds to the C-terminal -TESHHKAKGK motif of isolated bovine histone H2A. At physiological pH, the bound Ni(II) assists in hydrolysis of the E-S peptide bond in this motif that results in a cleavage of the terminal octapeptide SHHKAKGK off the histone's C-tail. To test if the hydrolysis could also occur in living cells, we cultured CHO (Chinese hamster ovary), NRK-52 (rat renal tubular epithelium), and HPL1D (human lung epithelium) cells with 0.1-1 mM Ni(II) for 3-7 days. As found by gel electrophoresis, Western blotting, and liquid chromatography/mass spectrometry, histones extracted from the cells contained a new fraction of histone H2A lacking the terminal octapeptide (q-H2A). The abundance of q-H2A increased with Ni(II) concentration and exposure time. It can be anticipated that the truncation of histone H2A may alter chromatin structure and affect gene expression. The present results provide evidence for novel mechanisms of epigenetic effects of Ni(II) that may be involved in nickel toxicity and carcinogenesis.
Karaczyn
Aldona A
AA
Laboratory of Comparative Carcinogenesis, NCI at Frederick, Frederick, Maryland 21702, USA.
Bal
Wojciech
W
North
Susan L
SL
Bare
Robert M
RM
Hoang
Van M
VM
Fisher
Robert J
RJ
Kasprzak
Kazimierz S
KS
D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D002273:Carcinogens / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D002417:Cattle; D002460:Cell Line; D002853:Chromatography, Liquid / Q000379:methods; D006224:Cricetinae; D015180:Electrophoresis, Gel, Two-Dimensional; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D009532:Nickel / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods
D002273:Carcinogens; D006657:Histones; D009842:Oligopeptides; D009532:Nickel