Increased sensitivity of DNA damage response-deficient cells to stimulated microgravity-induced DNA lesions

Microgravity is a major stress factor that astronauts have to face in space. In the past, the effects of microgravity on genomic DNA damage were studied, and it seems that the effect on genomic DNA depends on cell types and the length of exposure time to microgravity or simulated microgravity (SMG). In this study we used mouse embryonic stem (MES) and mouse embryonic fibroblast (MEF) cells to assess the effects of SMG on DNA lesions. To acquire the insight into potential mechanisms by which cells resist and/or adapt to SMG, we also included Rad9-deleted MES and Mdc1-deleted MEF cells in addition to wild type cells in this study. We observed significant SMG-induced DNA double strand breaks (DSBs) in Rad9-/- MES and Mdc1-/- MEF cells but not in their corresponding wild type cells. A similar pattern of DNA single strand break or modifications was also observed in Rad9-/- MES. As the exposure to SMG was prolonged, Rad9-/- MES cells adapted to the SMG disturbance by reducing the induced DNA ...微重力（Microgravity）是宇航员在太空中必须面对的主要应激因子。过往研究已针对微重力对基因组DNA损伤的影响展开探讨，现有结果显示，其对基因组DNA的作用效果取决于细胞类型以及暴露于微重力或模拟微重力（Simulated Microgravity, SMG）的时长。本研究采用小鼠胚胎干细胞（mouse embryonic stem, MES）与小鼠胚胎成纤维细胞（mouse embryonic fibroblast, MEF），以评估模拟微重力对DNA损伤的影响。为深入解析细胞抵御和/或适应模拟微重力的潜在机制，本研究除使用野生型细胞外，还纳入了Rad9基因敲除的小鼠胚胎干细胞与Mdc1基因敲除的小鼠胚胎成纤维细胞。本研究观察到，在Rad9⁻/⁻小鼠胚胎干细胞与Mdc1⁻/⁻小鼠胚胎成纤维细胞中，模拟微重力可诱导产生显著的DNA双链断裂（double strand breaks, DSBs），而对应的野生型细胞则未出现此类损伤。在Rad9⁻/⁻小鼠胚胎干细胞中也观察到了类似的DNA单链断裂或修饰模式。随着模拟微重力暴露时长延长，Rad9⁻/⁻小鼠胚胎干细胞可通过减少诱导产生的DNA……以适应模拟微重力的干扰。