Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
DNA Repair (Amst). 2019 Oct;82:102690. doi: 10.1016/j.dnarep.2019.102690. Epub 2019 Aug 24.
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.
将天然产物与化疗和/或放疗相结合可能会提高癌症治疗的疗效。有人假设，天然产物可能会抑制 DNA 修复，并使癌细胞对基于 DNA 损伤的癌症治疗敏感。然而，这些活性的分子机制尚不清楚。在这项研究中，我们发现二烯丙基二硫（DADS），一种有机硫化合物，增加了酵母细胞对 DNA 损伤的敏感性，并有潜力开发为基于 DNA 损伤的癌症治疗的辅助药物。我们通过向酵母中添加半乳糖诱导 HO 内切酶产生特定的 DNA 双链断裂（DSB），并使用该系统研究 DADS 如何影响 DNA 修复。在这项研究中，我们发现 DADS 抑制了单链退火（SSA）系统中的 DNA 修复，并使 SSA 细胞对单个 DSB 敏感。DADS 通过抑制 DNA 切除相关蛋白 Sae2 和 Exo1 的蛋白水平来阻碍 DNA 修复。我们还发现，DADS 阻止了 MRX 和 Mec1-Ddc2 复合物到 DSB 的募集。这一结果表明，DADS 以 Mec1（ATR）和 Tel1（ATM）依赖的方式拮抗 G2/M DNA 损伤检查点的激活。只有阐明 DADS 影响 DNA 修复的分子机制，我们才能发现新的辅助药物来改善化疗和/或放疗。
