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High-Mobility Group A1 Proteins Inhibit Expression of Nucleotide Excision Repair Factor Xeroderma Pigmentosum Group A

School of Molecular Biosciences, Washington State University, Pullman, Washington

Requests for reprints: Raymond Reeves, School of Molecular Biosciences, Washington State University, P. O. Box 644660, Pullman, WA 99164-4660. Phone: 509-335-1948; Fax: 509-335-9688; E-mail: reevesr{at}mail.wsu.edu.

Cells that overexpress high-mobility group A1 (HMGA1) proteins exhibit deficient nucleotide excision repair (NER) after exposure to DNA-damaging agents, a condition ameliorated by artificially lowering intracellular levels of these nonhistone proteins. One possible mechanism for this NER inhibition is down-regulation of proteins involved in NER, such as xeroderma pigmentosum complimentation group A (XPA). Microarray and reverse transcription-PCR data indicate a 2.6-fold decrease in intracellular XPA mRNA in transgenic MCF-7 cells overexpressing HMGA1 proteins compared with non–HMGA1-expressing cells. XPA protein levels are also 3-fold lower in HMGA1-expressing MCF-7 cells. Moreover, whereas a >2-fold induction of XPA proteins is observed in normal MCF-7 cells 30 min after UV exposure, no apparent induction of XPA protein is observed in MCF-7 cells expressing HMGA1. Mechanistically, we present both chromatin immunoprecipitation and promoter site-specific mutagenesis evidence linking HMGA1 to repression of XPA transcription via binding to a negative regulatory element in the endogenous XPA gene promoter. Phenotypically, HMGA1-expressing cells exhibit compromised removal of cyclobutane pyrimidine dimer lesions, a characteristic of cells that express low levels of XPA. Importantly, we show that restoring expression of wild-type XPA in HMGA1-expressing cells rescues UV resistance comparable with that of normal MCF-7 cells. Together, these data provide strong experimental evidence that HMGA1 proteins are involved in inhibiting XPA expression, resulting in increased UV sensitivity in cells that overexpress these proteins. Because HMGA1 proteins are overexpressed in most naturally occurring cancers, with increasing cellular concentrations correlating with increasing metastatic potential and poor patient prognosis, the current findings provide new insights into previously unsuspected mechanisms contributing to tumor progression. [Cancer Res 2007;67(13):6044–52]

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				L. Mao, K. J. Wertzler, S. C. Maloney, Z. Wang, N. S. Magnuson, and R. Reeves HMGA1 Levels Influence Mitochondrial Function and Mitochondrial DNA Repair Efficiency Mol. Cell. Biol., October 15, 2009; 29(20): 5426 - 5440. [Abstract] [Full Text] [PDF]