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Annals of Clinical & Laboratory Science 39:251-262 (2009)
© 2009 Association of Clinical Scientists

Truncation of Histone H2A’s C-terminal Tail, as Is Typical for Ni(II)-Assisted Specific Peptide Bond Hydrolysis, Has Gene Expression Altering Effects

Aldona A. Karaczyn1,*, Robert Y. S. Cheng2,*, Gregory S. Buzard3, James Hartley4, Dominic Esposito4 and Kazimierz S. Kasprzak1
1 Laboratory of Comparative Carcinogenesis and 2 Laboratory of Metabolism, Cellular Defense and Carcinogenesis Section, National Cancer Institute–Frederick, Frederick, Maryland; 3 Intramural Research Support Program and 4 Protein Expression Laboratory, SAIC–Frederick, Inc., Frederick, Maryland.

Address correspondence to Kazimierz S. Kasprzak, Ph.D., Laboratory of Comparative Carcinogenesis, Bldg. 538, Room 205E, National Cancer Institute at Frederick, Frederick, MD 21702, USA; tel 301 846 5738; fax 301 846 5946; e-mail kasprkaz{at}mail.ncifcrf.gov.

Nickel(II), capable of transforming cells and causing tumors in humans and animals, has been previously shown by us to mediate hydrolytic truncation of histone H2A’s C-terminal tail by 8 amino acids in both cell-free and cell culture systems. Since H2A’s C-tail is involved in maintaining chromatin structure, such truncation might alter this structure and affect gene expression. To test the latter possibility, we transfected cultured T-REx 293 human embryonic kidney cells with plasmids expressing either wild type (wt) or truncated (q) histone H2A proteins, which were either untagged or N-terminally tagged with fluorescent proteins. Each histone variant was found to be incorporated into chromatin at 24 and 48 hr post-transfection. Cells transfected with the untagged plasmids were tested for gene expression by microarray and real-time PCR. Evaluation of the results for over 21,000 genes using the multidimensional scaling and hierarchical clustering methods revealed significant differences in expression of numerous genes between the q-H2A and wt-H2A transfectants. Many of the differentially expressed genes, including BAZ2A, CLDN18, CYP51A1, GFR, GIPC2, HMGB1, IRF7, JAK3, PSIP1, and VEGF, are cancer-related genes. The results thus demonstrate the potential of q-H2A to contribute to the process of carcinogenesis through epigenetic mechanisms.

Keywords: histone H2A, nickel carcinogenesis, gene expression, cancer-related genes

Abbreviations: MES, 2-(-N-morpholino) ethanosulfonic acid; Ni(II), divalent nickel; q-H2A, truncated human histone H2A.1 lacking the SHHKAKGK C-terminal sequence; wt-H2A, wild-type human histone H2A.1; UHRR, Universal Human Reference RNA






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