Identification and characterization of a novel mechanism resulting in DNA Mismatch repair defects

• Applicant: Hans Hombauer, Ph.D.
• Subject Area: General Genetics and Functional Genome Biology ; Human Genetics ; Cell Biology
• Term: from 2015 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 279044692

The DNA Mismatch repair (MMR) pathway is an evolutionary conserved post-replicative mechanism that increases DNA replication fidelity by correcting errors introduced by DNA polymerases. Accordingly, mutations that inactivate the human MMR genes MSH2, MSH6, MLH1 and PMS2 are responsible of the most common hereditary cancer predisposition syndrome, referred as Lynch Syndrome or Hereditary Non-polyposis Colorectal Cancer (HNPCC). Lynch Syndrome is characterized by the accumulation of mutations across the whole genome, although more frequently observed at repetitive sequences or microsatellites. The increased accumulation of mutations results in the early-onset of cancer, resulting from the inactivation of tumor suppressor genes or activation of proto-oncogenes. Interestingly, about 5-10% of the colorectal cancer patients containing microsatellite unstable tumors, lack any mutations on the MMR genes, neither they show reduced protein expression levels for these MMR components. These observations suggest that besides inactivating mutations on the well-known MMR genes (or epigenetic silencing of their promoters), other still unidentified mechanisms should be responsible for the loss of MMR function in these patients.Recently, in a pilot screen in S. cerevisiae we have identified a novel mechanism that results in mismatch repair defects. The aim of this project is to unravel the underlying molecular mechanism resulting in loss of MMR function by using a combination of genetics, cellular and molecular biology and protein biochemistry; and to evaluate if these initial findings can be also extended to other model organisms like human cell lines and a mouse model. Since the MMR components are highly conserved from yeast to up to humans, we expect that this study might potentially provide a genetic causality for some of those patients with a microsatellite instability phenotype with no clear genetic or epigenetic abnormalities on MMR components.

• DFG Programme: Research Grants