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Glycobiology Advance Access originally published online on October 11, 2007
Glycobiology 2007 17(12):1357-1364; doi:10.1093/glycob/cwm105
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© The Author 2007. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

Modification of Topoisomerase I Activity by Glucose and by O-Glcnacylation of the Enzyme Protein

Noa Noach2, Yael Segev2, Itzhak Levi2, Shraga Segal2 and Esther Priel1,2

2 Shraga Segal Department of Microbiology and Immunology, Ben-Gurion University Cancer Research Center, Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva 84105, Israel

1 To whom correspondence should be addressed: Tel: 972-8-6479537; Fax: 972-8-6479579; e-mail: priel{at}bgu.ac.il

Received on May 29, 2007; revised on September 23, 2007; accepted on September 24, 2007

The regulation of topoisomerase I (topo I) activity is of prime importance for gene expression. It participates in DNA replication, transcription, recombination, and DNA repair, and serves as a target for anticancer drugs. Many proteins and enzymes are modified by O-linked ß-N-acetylglucosamine (O-GlcNAc), which exerts profound effects on their function. However, the modification of topo I by O-GlcNAc and the effect on its activity has not been previously reported. Here, we show that topo I protein is modified by O-GlcNAc in vitro in the porcine proximal tubular epithelial cell line (LLPCK-1), and in vivo in the mouse kidney. The level of O-GlcNAcylation of topo I protein correlates well with the enzyme activity, namely, a decrease in O-GlcNAc results in a reduction in topo I activity, and vice versa. O-GlcNAc transferase (OGT) was coprecipitated with topo I protein, suggesting a possible interaction between both enzymes. In addition, treatment of cells with glucosamine increased topo I activity and O-GlcNAcylation. The results of this study provide a novel mechanism for the regulation of topo I activity. Topo I is important for DNA transcription, therefore, its regulation by GlcNAcylation contributes to the mechanism by which glucose levels affect gene expression, and may pave the way to the development of new drugs that could control topo I activity.

Key words: DNA relaxation / glucose / O-GlcNAc / O-GlcNAc transferase (OGT) / topoisomerase I


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