Memory of DNA Damage

描述(由申请人提供)：暴露于DNA损害性侮辱，如高水平的ROS，紫外线或电离辐射，触发具有良好特征的P53介导的DNA损伤反应。这种反应导致细胞周期停滞和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。DNA损伤可能导致基因组改变，即使在DNA修复反应进行时也是如此。这可能会对经历DNA损伤的组织和有机体产生长期影响，某些细胞类型，特别是干细胞。我们之前已经发现，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，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胜过经历过较高水平损伤的细胞。因此，我们的结果表明，细胞可以记住过去发生的DNA损伤侮辱，即使在DNA修复反应完成之后也是如此。这项建议的目的是描述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会揭示一种新的机制，可以控制组织暴露在DNA破坏性侮辱下的长期后果。拟议的研究对于理解肿瘤发生的早期阶段也有明显的意义。 与公共健康相关：暴露在不同类型的压力下会诱导一种适应性应激反应程序，使细胞能够在侮辱中生存下来。某些形式的压力，特别是氧化应激、紫外线和电离辐射，会导致DNA损伤，进而触发DNA修复反应。我们发现，细胞可以跟踪过去导致DNA损伤的侮辱，而过去DNA损伤的相对程度决定了细胞在种群中的竞争状态。这个项目的目标是描述DNA损伤记忆的分子基础。拟议中的研究应该揭示一个重要的生物学机制，该机制决定了组织暴露在DNA破坏性侮辱下的长期后果。

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.