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; 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）：这项研究的目的是定义染色质在辐射诱导的双链断裂（DSB）过程中扮演的基本作用（DSB）。细胞存活和基因组完整性的维持至关重要的取决于DSB的修复。如果修复错误，DSB会导致诸如染色体重排的像差，并可能导致癌症的形成。为了充分了解辐射引起的DSB的修复，重要的是要考虑自然情境 - 染色质。基因组中染色质的包装可能会通过类似于基因表达的情况来影响DNA修复过程。因此，我们发现在修复辐射诱导的，内源性和发育过程的DNA损伤后，染色质组装因子ASF1和CAF-1对于细胞存活至关重要。此外，我们最近首次表明，在DSB修复过程中，组蛋白乙酰化通过同源重组途径在本地发生变化，并且如果细胞在DSB修复期间无法改变其乙酰化状态，它们就会死亡。我们将检验以下假设：在维修过程中，染色质的组蛋白，重塑，拆卸和重新组装的特定后翻译后修饰。此外，我们将定义分子机制，说明为什么这些染色质动力学对于染色体修复至关重要且内在。最后，我们将确定对DSB修复至关重要的新型染色质修饰。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中高度特异性的内切酶，以研究独特定义的DSB下的分子事件。使用此模型系统，我们将绘制在伴随DSB之前的染色质结构的更改。拟议的实验的发现将为理解染色质结构在辐射诱导的DSB时的基本且知之甚少的作用提供基础。因此，这些研究直接适用于辐射引起的基因组完整性丧失（包括多种形式的癌症）导致的人类疾病。