A novel DNA repair inhibitor,diallyl disulfide (DADS), impairs DNA resection during DNA double-strand break repair by reducing Sae2 and Exo1 levels |
| |
| Institution: | 1. Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan;2. Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, Taiwan;3. Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan;4. Tissue Bank, Chang Gung Memorial Hospital, Taoyuan, Taiwan;5. Graduate Institute of Health Industry Technology, Research Center for Industry of Human Ecology, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan;6. Liver Research Center, Chang Gung Memorial Hospital, Linko, Taiwan;7. Department of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan;1. Graduate School of Life Sciences, Tohoku University, Sendai, Japan;2. Frontier Research Institute for Interdisciplinary Sciences, Tohoku University, Sendai, Japan;1. University of Illinois College of Medicine, Department of Biomedical Sciences, Rockford, IL, 61107, United States;2. University of Illinois College of Pharmacy, Biopharmaceutical Sciences Department, Rockford IL, 61107, United States;1. State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060, China;2. School of Basic Medical Science, Guangzhou Medical University, Guangzhou, 511436, China;3. The Sixth Affiliated Hospital, Guangzhou Medical University, Qingyuan, 511518, China;1. Department of Biology, University of Iowa, Iowa City, IA 52242, USA;2. Indiana University Purdue University Indianapolis (IUPUI), Indianapolis, IN 46202, USA;3. Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA;1. Cancer Epigenetics and Cancer Biology Programs, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA;2. Department of Biomedical Sciences, University of Sassari, Sassari, 07100, Italy;3. Proteomics Core, The Children’s Hospital of Philadelphia, Philadelphia PA, 19104, USA;4. Cancer Biology Programs, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA;5. Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA;6. Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, 19122, USA |
| |
| Abstract: | Combining natural products with chemotherapy and/or radiotherapy may increase the efficacy of cancer treatment. It has been hypothesized that natural products may inhibit DNA repair and sensitize cancer cells to DNA damage-based cancer therapy. However, the molecular mechanisms underlying these activities remain unclear. In this study, we found that diallyl disulfide (DADS), an organosulfur compound, increased the sensitivity of yeast cells to DNA damage and has potential for development as an adjuvant drug for DNA damage-based cancer therapy. We induced HO endonuclease to generate a specific DNA double-strand break (DSB) by adding galactose to yeast and used this system to study how DADS affects DNA repair. In this study, we found that DADS inhibited DNA repair in single-strand annealing (SSA) system and sensitized SSA cells to a single DSB. DADS impaired DNA repair by inhibiting the protein levels of the DNA resection-related proteins Sae2 and Exo1. We also found that the recruitment of MRX and the Mec1-Ddc2 complex to a DSB was prevented by DADS. This result suggests that DADS counteracts G2/M DNA damage checkpoint activation in a Mec1 (ATR)- and Tel1 (ATM)-dependent manner. Only by elucidating the molecular mechanisms by which DADS influences DNA repair will we be able to discover new adjuvant drugs to improve chemotherapy and/or radiotherapy. |
| |
| Keywords: | Diallyl disulfide DNA repair Homologous recombination DNA resection DNA damage checkpoint |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
