Nucleic Acids Research, 2003, Vol. 31, No. 23 6841-6851
© 2003 Oxford University Press
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High mobility group A2 protein and its derivatives bind a specific region of the promoter of DNA repair gene ERCC1 and modulate its activity
Center for Human Genetics, University of Bremen, Leobenerstr. ZHG, D-28359 Bremen, Germany, 1 III. Zoologisches Institut-Entwicklungsbiologie, Universität Göttingen, Humboldtallee 34A, D-37073, Germany and 2 Edward A. Doisy Department of Biochemistry and Molecular Biology, St Louis University, Medical School, St Louis, MO 63104, USA
*To whom correspondence should be addressed at present address: Tel: +1 301 594 6670; Fax: +1 301 435 3697; Email: ralf.schwanbeck{at}gmx.net
Present addresses:
Ralf Schwanbeck, NIH, National Cancer Institute, Building 37, Room 6060B, Bethesda, MD 20892-4255, USA
Piere Rogalla, alcedo biotech GmbH, Leobenerstrasse, ZHG, D-28359 Bremen, Germany
Jacek R. Wi
niewski, MDS Inc., Denmark, Stærmosegårdsvej 6, DK5230 Odense M, Denmark
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors
High mobility group A2 (HMGA2) chromosomal non-histone protein and its derivatives play an important role in development and progression of benign and malignant tumors, obesity and arteriosclerosis, although the underlying mechanisms of these conditions are poorly understood. Therefore, we tried to identify target genes for this transcriptional regulator and to provide insights in the mechanism of interaction to its target. Multiple genes have been identified by microarray experiments as being transcriptionally regulated by HMGA2. Among these we chose the ERCC1 gene, encoding a DNA repair protein, for this study. DNA-binding studies were performed using HMGA2 and C-terminally truncated 
HMGA2, a derivative that is frequently observed in a variety of tumors. A unique high affinity HMGA2 binding site was mapped to a specific AT-rich region located –323 to –298 upstream of the ERCC1 transcription start site, distinguishing it from other potential AT-rich binding sites. The observed 1:1 stoichiometry for the binding of wild-type HMGA2 to this region was altered to 1:2 upon binding of truncated HMGA2, causing DNA bending. Furthermore, the regulatory effect of HMGA2 was confirmed by luciferase promoter assays showing that ERCC1 promoter activity is down-regulated by all investigated HMGA2 forms, with the most striking effect exerted by HMGA2. Our results provide the first insights into how HMGA2 and its aberrant forms bind and regulate the ERCC1 promoter.
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