Memory of DNA Damage

DNA损伤记忆

基本信息

批准号：
8451507
负责人：
Ruslan Medzhitov
金额：
$ 32.36万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-01 至 2016-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8451507
关键词：
Acute Address Affect Age Apoptosis Area Biochemical Biological Cell Aging Cell Cycle Cell Cycle Arrest Cell Proliferation Cells ChIP-seq Chronic Complex DNA DNA Damage DNA Double Strand Break DNA Repair DNA biosynthesis DNA damage checkpoint Data Dose Environment Epigenetic Process Exposure to Gene Expression Gene Expression Profile Genes Genome Genomics Goals Growth Growth Factor Hematopoietic Hematopoietic stem cells Image Ionizing radiation Kinetics Link Maintenance Mediating Memory Molecular Molecular Biology Molecular Genetics Nature Nonhomologous DNA End Joining Organism Oxidative Stress Physiological Population Proliferating Relative (related person)Role Signal Transduction Specificity Staging Stem cells Stimulus Stress Testing Time Tissues Ultraviolet Rays Withdrawal base biological adaptation to stress cancer initiation cell injury cell type cytotoxic design expectation experience homologous recombination in vivo insight irradiation novel programs public health relevance research study response senescence stem cell population tumorigenesis

项目摘要

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.

描述（由申请人提供）：暴露于DNA损害损伤的损伤，例如高水平的ROS，紫外线或电离辐射，会触发良好的p53 p53介导的DNA损伤响应。这种反应导致细胞周期停滞和DNA修复或凋亡，具体取决于细胞类型，增殖状态和DNA损伤程度。即使参与DNA修复反应，DNA损伤也会导致基因组改变。这可能会对经历DNA损害某些细胞类型的组织和生物的组织和生物产生长期后果，尤其是在干细胞中。我们以前已经发现，造血干细胞可以长时间（几个月至一年）跟踪过去的DNA损伤，并且过去DNA损伤的相对程度决定了其竞争状况，从而使过去DNA损伤水平相对较低的细胞超过造成更高损害的细胞。因此，我们的结果表明，即使在完成DNA修复响应后，细胞也可以记住过去发生的DNA破坏损伤。该建议的目的是表征DNA损伤记忆的分子机制。我们的初步研究和提出的实验应揭示一种新的机制，该机制控制着组织暴露于DNA受损损伤的长期后果。拟议的研究也对理解肿瘤发生的早期阶段具有明显的影响。