The Study of Sensitizing Cells to Dna Damage by Targeting Homologous Recombination Pathway

Targeting DNA repair pathways is an increasingly popular strategy for improving the efficacy of DNA damage-based cancer therapy such as chemotherapy and radiotherapy. Moreover, it has been reported that DNA repair inhibition is a promising strategy for personalized cancer therapy which could be selective for tumor cells and have fewer side effects. In this project, we will first exploit the functional conservation of the DNA repair pathways between yeast and humans to mechanistically identify inhibitors of DNA repair proteins in yeast. However, experimentally, the sequence-independent nature of damaging drug treatment (chemotherapeutic treatment) or radiation-induced damage makes it difficult to study DNA repair. Therefore, we used a single-strand annealing (SSA) system where we can induce a double-strand break (DSB) at specific site to study the kinetics of DNA repair following BAK treatment in yeast. Our preliminary data showed that Bakuchiol (BAK) increased the sensitivity of yeast cells to DNA damage and may have potential to develop as a combined drug to chemotherapy/radiotherapy or a drug for personalized therapy. Therefore, we will first use the SSA system to elucidate the molecular mechanisms of how BAK improve DNA damage sensitivity in yeast and furthermore extend to human cancer cells. Next, we will verify the molecular mechanism in mice xenografts. Hopefully, we will support the preclinical relevance of identifying molecular targets for DNA damage repair proteins that will be of paramount importance in devising future therapeutic interventions.

Project ID:PC10901-2283
External Project ID:MOST107-2320-B182-026-MY3