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Induction of the alkyltransferase (MGMT) gene by DNA damaging agents and the glucocorticoid dexamethasone and comparison with the response of base excision repair genes |
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| Authors: | Grombacher, Thomas Mitra, Sankar Kaina, Bernd |
| Affiliation: | 1Division of Applied Toxicology, Institute of Toxicology, University of Mainz Obere Zahlbacher Strasse 67, D-55131 Mainz, Germany 2Institute of Genetics, Research Center Karlsruhe PF 3640, D-76021 Karlsruhe, Germany 3Sealy Center for Molecular Science, The University of Texas Medical Branch Galveston, TX 77555-1068, USA |
| Abstract: | Repair of alkylated bases in DNA is performed by O6-methylguanine-DNAmethyltransferase (MGMT) and a set of enzymes of the base excisionrepair pathway involving N-methylpurine-DNA glycosylase (MPG),apurinic endonuclease (APE), DNA polymerase ß (Polß) and DNA ligase. The level of expression of theseenzymes may exert a profound effect on resistance of cells towardsalkylating drugs. We have comparatively analyzed the expressionof MGMT and the different base excision repair genes in rathepatoma cells (line H4IIE) after exposure to alkylating agents,X-rays and the glucocorticoid hormone dexamethasone. Furthermore,the effect of these agents on the activity of the cloned humanMGMT promoter was assayed. Exposure of cells to N-methyl-N'-nitro-N-nitrosoguanidine(MNNG) or ionizing radiation increased MGMT mRNA levels up to4.5-fold. Under the same conditions of treatment, exerting onlya weak toxic effect, MPG and DNA ligase I mRNA levels were notenhanced, whereas the amounts of APE and Pol ß mRNAtransiently increased by |
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