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
Call for proposal
See other projects for this call