GEnome INstABiLity SyndromEs as a Toolbox to Unravel Novel DNA Repair Pathways (ENABLE)

• Applicants: Professor Dr. Arndt Borkhardt; Dr. Ron Jachimowicz; Professor Dr. Tobias Marschall; Professorin Dr. Dagmar Wieczorek
• Subject Area: Human Genetics ; Hematology, Oncology ; Cell Biology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 496874193

Defects in DNA repair pathways promote genome instability and are a central contributor to carcinogenesis. The overarching goal of this collaborative project is to characterize novel cancer signalling pathways based on human genome instability syndromes and to extract therapeutic approaches for cancer based on the molecular liabilities discovered within this research program. To that end, the applicants will launch a prospective genome instability syndrome patient cohort. Patients will be screened based on an adapted filter of clinical phenotypes, that are associated with genome instability. Next, we will utilize next generation sequencing on our patient cohort to find genes and pathways involved in genome instability in combination with a bioinformatic algorithm to enhance the identification of DNA damage response (DDR) relevant gene alterations. Finally, we will validate candidate gene alterations in DNA repair assays in vitro. For that, we will carry out mechanistic studies utilizing a high-throughput experimental pipeline consisting of high-throughput viability assays following DNA damage, automated immunofluorescence to measure capacity and the function of DNA repair as well as DNA repair fluorescent reporter assays to explore aberrant DNA repair pathways. By implementing these three steps, we generate a reciprocal relationship between the cohort assembly, the DDR-specific bioinformatics pipeline and the functional validation. Generated knowledge is likely to result in synergies that will lead to iterative improvements across all three streams (e.g., knowledge gained in the functional validation experiments will update the DDR algorithm). Overall, this consortium aims to build a genome instability cohort of 75 patients within the proposed two years of this funding period. This will lead to the identification of novel DDR pathways that can be exploited for cancer therapies.

• DFG Programme: Research Grants