Memory of DNA Damage

描述（由申请人提供）：暴露于DNA损伤损伤，如高水平的活性氧、紫外线或电离辐射，会触发典型的p53介导的DNA损伤反应。这种反应导致细胞周期阻滞和DNA修复或凋亡，这取决于细胞类型、增殖状态和DNA损伤的程度。即使DNA修复反应参与，DNA损伤也会导致基因组改变。这可能会对经历DNA损伤的组织和生物体产生长期影响，特别是在干细胞中。我们之前发现，造血干细胞可以在很长一段时间内（几个月到一年）跟踪过去的DNA损伤，并且这种过去DNA损伤的相对程度决定了它们的竞争地位，因此，过去DNA损伤水平相对较低的细胞比经历过较高水平损伤的细胞更具竞争力。因此，我们的研究结果表明，即使在DNA修复反应完成后，细胞也能记住过去发生的DNA损伤损伤。这一建议的目的是表征DNA损伤记忆的分子机制。我们的初步研究和拟议的实验应该揭示一种控制组织暴露于DNA损伤损伤的长期后果的新机制。所提出的研究对了解肿瘤发生的早期阶段也有明显的意义。

DESCRIPTION (provided by applicant): Exposure to DNA damaging insults, such as high level of ROS, UV or ionizing radiation, triggers a well-characterized p53 mediated DNA damage response. This response leads to cell cycle arrest and DNA repair or apoptosis, depending on cell type, proliferative status and the extent of DNA damage. DNA damage can result in genome alterations even when DNA repair response is engaged. This may have long-term consequences for the tissue and organism that experienced DNA damage certain cell types, particularly in stem cells. We have previously found that hematopoietic stem cells can keep track of the past DNA damage for extended periods of time (months to a year) and the relative extent of this past DNA damage determines their competitive status, such that cells with relatively lower levels of past DNA damage outcompete cells that had experienced higher level of damage. Thus our results suggest that cells can remember the DNA damaging insults that happen in the past, even after the DNA repair response has been completed. The purpose of this proposal is to characterize the molecular mechanisms of the memory of DNA damage. Our preliminary studies and proposed experiments should reveal a novel mechanism that controls long-term consequences of tissue exposure to DNA damaging insults. The proposed studies also have obvious implications for the understanding of early stages of tumorigenesis. PUBLIC HEALTH RELEVANCE: Exposure to different types of stress induces an adaptive stress response program that enables the cells to survive the insult. Some forms of stress, notably oxidative stress, UV and ionizing radiation, cause DNA damage, which in turn triggers DNA repair response. We found that cells can keep track of the past insults resulting in DNA damage and the relative extent of the past DNA damage determines the cells competitive status within a population. The goal of this project is to characterize the molecular basis of the memory of DNA damage. The proposed studies should reveal an important biological mechanism that determines the long-term consequences of tissue exposure to DNA damaging insults.