IMMR

Mechanisms of Mismatch repair inactivation and identification of genes suppressing mutations

Coordinatore	DEUTSCHES KREBSFORSCHUNGSZENTRUM    more  Organization address address: Im Neuenheimer Feld 280 city: HEIDELBERG postcode: 69120 contact info Titolo: Dr. Nome: Ina Cognome: Wiest Email: send email Telefono: +49 6221 422700 Fax: +49 6221 422708
Nazionalità Coordinatore	Germany [DE]
Totale costo	100˙000 €
EC contributo	100˙000 €
Programma	FP7-PEOPLE Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
Code Call	FP7-PEOPLE-2013-CIG
Funding Scheme	MC-CIG
Anno di inizio	2014
Periodo (anno-mese-giorno)	2014-04-01   -   2018-03-31

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	DEUTSCHES KREBSFORSCHUNGSZENTRUM  Organization address address: Im Neuenheimer Feld 280 city: HEIDELBERG postcode: 69120 contact info Titolo: Dr. Nome: Ina Cognome: Wiest Email: send email Telefono: +49 6221 422700 Fax: +49 6221 422708	DE (HEIDELBERG)	coordinator	100˙000.00

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 Obiettivo del progetto (Objective)

'The fidelity of DNA replication, and therefore the stability of the genome, relies on the DNA Mismatch repair (MMR) pathway, which recognizes DNA replication errors and promotes repair by an excision and re-synthesis mechanism. Mutations that inactivate MMR are associated to Lynch Syndrome, an early-onset cancer disorder characterized by accumulation of mutations at repetitive sequences or microsatellite instability (MSI). Interestingly, a significant number of tumors with MSI have not been correlated with MMR defects, suggesting that additional factors may influence MMR proficiency or DNA replication fidelity The current proposal aims to investigate alternative molecular mechanisms that result in MMR inactivation and to identify unrecognized genes that are essential for suppression of mutations. We will characterize a subset of Msh6 dominant mutations that abolishes MMR function by inactivating the partially redundant Msh2-Msh3 pathway. Furthermore, we will carry out a genetic screen to identify dominant mutations on the MMR-related genes: MSH3, MLH2 and MLH3 that result in MMR inactivation. Finally, we will carry out a genome-wide screen in budding yeast, to identify mutants that results in increased mutation rates. The human homologs of the identified yeast genes will be further characterized in human cell lines by knock-down experiments and in vivo mutator assays. This proposal is directed to achieve a better understanding of mechanisms preventing accumulation of mutations and will provide relevant information for diagnosis of cancer susceptibility syndromes.'