Community Research and Development Information Service - CORDIS

Final Report Summary - IMMR (Mechanisms of Mismatch repair inactivation and identification of genes suppressing mutations)

Every living organism has the necessity to preserve to a large extent the stability of the genetic information contained within the DNA. Changes in the genetic information (mutations) caused by external agents (e.g. chemicals or radiations) or produced as result of normal cellular metabolism (e.g. DNA replication, oxidative damage, etc.) are deleterious as they frequently result in alterations in gene function. Importantly, mutations are the cause of human genetic disorders including cancer. The maintenance of the stability of the genome is sustained by a variety of surveillance mechanisms and DNA repair pathways that prevent the accumulation of mutations, among other types of DNA insults. As part of this project, we aimed to identify previously unrecognized genes that are important for genome stability. To discover these potential genes, we designed a genetic screen using budding yeast as a model organism. As result, we identified a group of genes that have not been previously associated to the suppression of mutations. Our studies demonstrate that some of them are required for the synthesis of deoxyribonucleoside triphosphates (dNTPs), the building blocks of DNA. Inactivation of these genes leads to alterations in the intracellular dNTP concentrations and mutator phenotypes. The most relevant findings of this project have been made public in recent publication in the journal Proceedings of the National Academy of Sciences of the USA (Schmidt et al., 2017 PNAS).
In the second part of this project, we aimed to characterize a group of mutations that interfere with the DNA mismatch repair (MMR) system. The MMR system exist in almost all living organisms and plays an important role during the correction of DNA replication errors introduced during the duplication of the genome. In humans, mutations causing the inactivation this DNA repair pathway are linked to cancer, as observed in Lynch Syndrome (also called hereditary non-polyposis colorectal cancer or HNPCC). Patients with this deficiency tend to accumulate large number of mutations, especially at repetitive sequences or microsatellites (microsatellite instability) and show early-onset of colorectal, ovarian and endometrial cancer (among others). Interestingly, 5-10% of colorectal cancer patients containing microsatellite unstable tumors do not present mutations in MMR genes, neither show alterations in their expression pattern. These observations suggest that besides mutations inactivating MMR genes, other still unidentified mechanisms could be responsible for the loss of MMR function in these patients. By using a candidate-based approach, we have identified specific dominant mutations in a poorly characterized gene, which resulted in partial loss of MMR function in yeast or human cells. Current efforts of our team aims to unravel the molecular mechanism how this mutant protein prevents MMR function.
In summary, we have used budding yeast as model organism to identify novel genes that contribute to the stability of the genome. Given the fact that most of the identified genes play functions that are conserved across yeast and human, our research predict that inactivation of the human homolog genes might be associated to cancer predisposition. This hypothesis needs to be further tested in future studies. The knowledge obtained from our research might be useful for early detection, genetic counseling of patient carriers and potential treatment strategies.
Thanks to the financial support obtained from the European Commission, Marie Curie Integration Grant (CIG), together with other funds obtained from other sources, it was possible to identify and characterize novel genetic factors that might predispose to human cancer. Certainly, the CIG grant has been an important tool that enhanced my career development and my chances during a future tenure-track evaluation process.

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Life Sciences
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