Project description DEENESFRITPL Is there a link between diet and DNA damage? There are many reports underscoring the association between nutrition and cancer risk, but the underlying mechanisms remain elusive. The EU-funded METAREPAIR project will work on the hypothesis that high-fat diets affect DNA repair processes, leading to genomic instability and epigenetic marks such as histone and RNA methylation. Researchers will conduct experiments on prostate cancer cells and determine how manipulation of key metabolites affects these epigenetic marks and DNA repair. Apart from fundamental knowledge, results will have translational impact and pave the way for precision nutrition interventions as an anticancer treatment. Show the project objective Hide the project objective Objective Preclinical and epidemiological studies indicate that some dietary patterns, such as high-fat diet (HFD), are associated with increased risk for many cancers, including prostate cancer (PCa). However, our mechanistic understanding of the link between diet and cancer remains limited. To help deconvolute the connection between nutrition and tumorigenesis, METAREPAIR will investigate the role of genomic instability in mediating the effect of nutritional metabolism on PCa aggressiveness. I hypothesize that the oncogenicity of ‘HFD-like’ diets is in part due to a diet-induced erosion of DNA repair capacity caused by altered epigenetic and epitranscriptomic landscapes. Based on enticing preliminary data indicating that diet-dependent alterations of one carbon metabolites can impact DNA damage repair efficacy and DNA repair-pathway choice, I present a model whereby changes in nutritional metabolism affect the activity of writers and erasers of histone and RNA methylation marks and consequently impair their role in orchestrating DNA damage repair. I will test this model by manipulating in vitro the levels of key metabolites and then use an innovative experimental toolkit to assess the dynamics of DNA repair in PCa cells. The effect of metabolic manipulation onto DNA repair will be studied through the mechanistic lens of RNA and histone methylation. This diet-DNA damage link will be tested in vivo as a tool for precision nutrition intervention to sensitize PCa tumours to DNA-damaging therapies. The findings of METAREPAIR could unveil a yet-unexplored link between metabolic perturbations and genomic stability, with far reaching implications at fundamental as well as translational level. By allowing me to deliver innovative science in both the applied and basic aspects of DNA repair and RNA role in it, METAREPAIR represents a career-changing opportunity that will place me in a strong position to pursue my next career step of becoming an independent researcher. Fields of science medical and health sciencesclinical medicineoncologyprostate cancernatural sciencesbiological sciencesgeneticsDNAmedical and health scienceshealth sciencesnutritionnatural sciencesbiological sciencesgeneticsRNA Keywords cancer metabolism high-fat diet DNA damage response DNA repair epigenetics epitranscriptomics Programme(s) H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions Main Programme H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility Topic(s) MSCA-IF-2020 - Individual Fellowships Call for proposal H2020-MSCA-IF-2020 See other projects for this call Funding Scheme MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF) Coordinator IFOM-ISTITUTO FONDAZIONE DI ONCOLOGIA MOLECOLARE ETS Net EU contribution € 171 473,28 Address VIA ADAMELLO 16 20139 Milano Italy See on map Region Nord-Ovest Lombardia Milano Activity type Research Organisations Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 171 473,28
