|Title / Titel||The Role of the Mismatch Repair System in DNA Damage Signalling: Relevance to Drug Resistance in the Therapy of Colon Cancer|
|Abstract (PDF, 14 KB)|
|Summary / Zusammenfassung||During the past years, we have been studying the link between colon cancer and a defect in the mismatch repair (MMR) system. Families with mutations in MMR genes, the so-called hereditary non-polyposis colon cancer (HNPCC) kindred, are predisposed to cancer of the colon, endometrium and ovary. Although ovarian cancer is successfully treated with cisplatin, MMR-deficient cells are more than 2-fold resistant to this agent. We wish to understand the mechanism underlying this phenomenon, and propose to focus on the DNA damage signalling pathways that are selectively triggered by cisplatin in MMR-proficient cells. In the past, the response of human cells to DNA damaging agents has been studied exclusively in vivo. As cell-free MMR assays are in routine use in our laboratory, we decided to exploit the possibility of activating the signalling pathways in extracts of vertebrate cells. We shall do this by incubating extracts of MMR-proficient and –deficient cells (either treated or not with DNA damaging agents) with a variety of hetero- and homoduplex substrates, in the presence of specific inhibitors of selected protein kinases (e.g. ATM/ATR, CHK1). We shall then analyse the post-translational modification status of selected substrates of these kinases. It is envisaged that the identification of pathways specifically activated in human cells by cisplatin in a MMR-dependent manner might help us elucidate the molecular mechanisms of cytotoxicity of this substance, and to develop novel therapies that might selectively kill MMR-deficient cells.
|Publications / Publikationen||Jiricny J, Marra G.
DNA repair defects in colon cancer
Curr Opin Genet Dev., 13, 61-9, 20035-Fluorouracil is Efficiently Removed from DNA by the Base Excision and Mismatch Repair Systems.
Fischer, F., Baerenfaller, K. and Jiricny, J. (2007) Gastroenterology, in pressWeitere Informationen
|Keywords / Suchbegriffe||mismatch repair, DNA damage signalling, HNPCC, colon cancer|
|Project leadership and contacts /
Projektleitung und Kontakte
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|Duration of Project / Projektdauer||Oct 2003 to Sep 2005|