Chromatin's Role in Repair of Radiation-induced Damage.

染色质在修复辐射引起的损伤中的作用。

• 批准号: 7210170
• 负责人: Jessica K Tyler
• 金额: $ 26.86万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7210170
• 关键词: DNA damage; DNA repair; DNA replication; chromatin; chromosome aberrations; developmental genetics; endonuclease; enzyme induction /repression; eukaryote; fungal genetics; gene expression; gene targeting; genetic manipulation; genetic mapping; genetic models; histones; protein biosynthesis; protein structure function; radiation genetics; radiation sensitivity; yeasts

DESCRIPTION (provided by applicant): The goal of this research is to define the fundamental role that chromatin plays during the repair of radiation-induced double-strand breaks (DSBs). Cell survival and maintenance of genome integrity are critically dependent on the repair of DSBs. If repaired incorrectly, DSBs result in aberrations such as chromosomal rearrangements and can lead to formation of cancers. In order to fully understand the repair of radiation-induced DSBs, it is important to consider the natural context - chromatin. The packaging of the genome into chromatin is likely to influence DNA repair processes by analogy to the situation with gene expression. Accordingly, we have discovered that the chromatin assembly factors Asf1 and CAF-1 are essential for cell survival following the repair of radiation-induced, endogenous and developmentally-programmed DNA damage in vivo. Furthermore, we have recently shown for the first time that histone acetylation changes locally during DSB repair via the homologous recombination pathway, and that cells die if they cannot change their acetylation state during DSB repair. We will test the hypothesis that specific post- translational modifications of histones, remodeling, disassembly, and reassembly of the chromatin occur at the DSB during repair. Furthermore, we will define the molecular mechanism as to why these chromatin dynamics are essential and intrinsic to chromosomal repair. Finally, we will identify novel chromatin modifications that are critical for DSB repair. In order to gain insight into the repair of radiation-induced DNA damage, the approach will be to synchronously induce a highly specific endonuclease within yeast to study the molecular events at a unique defined DSB. Using this model system, we will map the changes to the chromatin structure that precede, accompany and follow the repair of a DSB. The findings of the proposed experiments will provide the foundation for understanding the fundamental, yet poorly understood, role of chromatin structure during the repair of radiation-induced DSBs. As such, these studies are directly applicable to human diseases that result from radiation-induced loss of genome integrity, including many forms of cancer.

描述（由申请人提供）：本研究的目的是确定染色质在辐射诱导的双链断裂（DSB）修复过程中发挥的基本作用。细胞存活和基因组完整性的维持严重依赖于DSB的修复。如果修复不当，DSB会导致染色体重排等畸变，并可能导致癌症的形成。为了充分理解辐射诱导的DSB的修复，重要的是要考虑自然背景-染色质。将基因组包装到染色质中可能会影响DNA修复过程，这与基因表达的情况类似。因此，我们已经发现，染色质组装因子Asf 1和CAF-1是必不可少的细胞存活后，修复辐射诱导的，内源性的和发育程序性的DNA损伤在体内。此外，我们最近首次表明，组蛋白乙酰化在DSB修复过程中通过同源重组途径局部变化，如果细胞在DSB修复过程中不能改变其乙酰化状态，则细胞死亡。我们将检验这样的假设，即在修复过程中，组蛋白的特定翻译后修饰、染色质的重塑、分解和重组发生在DSB。此外，我们将定义的分子机制，为什么这些染色质动力学是必不可少的和内在的染色体修复。最后，我们将确定新的染色质修饰是DSB修复的关键。为了深入了解辐射诱导的DNA损伤的修复，该方法将是同步诱导酵母内的高度特异性核酸内切酶，以研究在一个独特的定义DSB的分子事件。使用这个模型系统，我们将映射的染色质结构的变化之前，伴随和跟随修复的DSB。拟议的实验结果将提供基础，了解基本的，但知之甚少，染色质结构的作用，在辐射诱导的DSB的修复过程中。因此，这些研究可直接应用于因辐射引起的基因组完整性丧失而导致的人类疾病，包括许多形式的癌症。