Targeting Dna Repair Pathways by Dads to Enhance Dna Damage Senitivity

Effective DNA repair enables cancer cells to survive from DNA damage that is induced by chemotherapeutic or radiotherapeutic treatments. Therefore, the screening of DNA repair inhibitors is a new therapeutic strategy to increase the efficacy of such treatments. 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. Our preliminary data showed that Diallyl disulfide (DADS), an organosulfur derived from garlic, 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. 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 DADS treatment in yeast. We have preliminarily found that DADS inhibited DSB repair suggesting that DADS may increase DNA damage sensitivity by inhibiting DSB repair in yeast. In this project, we will first use the SSA system to elucidate the molecular mechanisms of how DADS improve DNA damage sensitivity in yeast and furthermore extend to human cancer cells. Next, we will verify the molecular mechanism in mice xenografts. Targeting DNA repair pathways is an increasingly popular strategy for improving the efficacy of DNA damage-based cancer therapy as well as for personalized cancer therapy. In this project, 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:PC10608-1818
External Project ID:MOST106-2320-B182-015