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J. Biol. Chem., Vol. 280, Issue 37, 32184-32192, September 16, 2005

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Inhibition of Nucleotide Excision Repair by High Mobility Group Protein HMGA1^*

From the School of Molecular Biosciences, Biochemistry, and Biophysics, Washingston State University, Pullman, Washington 99164-4660

The mammalian non-histone "high mobility group" A (HMGA) proteins are the primary nuclear proteins that bind to the minor groove of AT-rich DNA. They may, therefore, influence the formation and/or repair of DNA lesions that occur in AT-rich DNA, such as cyclobutane pyrimidine dimers (CPDs) induced by UV radiation. Employing both stably transfected lines of human MCF7 cells containing tetracycline-regulated HMGA1 transgenes and primary Hs578T tumor cells, which naturally overexpress HMGA1 proteins, we have shown that cells overexpressing HMGA1a protein exhibit increased UV sensitivity. Moreover, we demonstrated that knockdown of intracellular HMGA1 concentrations via two independent methods abrogated this sensitivity. Most significantly, we observed that HMGA1a overexpression inhibited global genomic nucleotide excision repair of UV-induced CPD lesions in MCF-7 cells. Consistent with these findings in intact cells, DNA repair experiments employing Xenopus oocyte nuclear extracts and lesion-containing DNA substrates demonstrated that binding of HMGA1a markedly inhibits removal of CPDs in vitro. Furthermore, UV "photo-foot-printing" demonstrated that CPD formation within a long run of Ts (T₁₈-tract) in a DNA substrate changes significantly when HMGA1 is bound prior to UV irradiation. Together, these results suggest that HMGA1 directly influences both the formation and repair of UV-induced DNA lesions in intact cells. These findings have important implications for the role that HMGA protein overexpression might play in the accumulation of mutations and genomic instabilities associated with many types of human cancers.

Received for publication, May 23, 2005 , and in revised form, July 12, 2005.

^* This work was supported by National Institutes of Health (NIH) Grants ES02614 (to M. J. S.), GM071760 (to R. R. and M. J. S.), and GM46352 (to R. R.), by Washington State University Cancer Research Development Fund Grant 17A-0165 (to R. R.), and by NIH Grant T-32 GM008336 for predoctoral training in biotechnology (to J. E. A). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² Present address: Dept. of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520.

³ To whom correspondence may be addressed. Tel.: 509-335-6853; Fax: 509-335-9688; E-mail: smerdon{at}mail.wsu.edu. ⁴ To whom correspondence may be addressed. Tel.: 509-335-1948; Fax: 509-335-9688; E-mail: reevesr{at}wsu.edu.

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				J. E. Adair, S. C. Maloney, G. A. Dement, K. J. Wertzler, M. J. Smerdon, and R. Reeves High-Mobility Group A1 Proteins Inhibit Expression of Nucleotide Excision Repair Factor Xeroderma Pigmentosum Group A Cancer Res., July 1, 2007; 67(13): 6044 - 6052. [Abstract] [Full Text] [PDF]