DNA Double Strand Break Chromatin Alterations and Genome Integrity

DNA 双链断裂染色质改变和基因组完整性

基本信息

批准号：
8820272
负责人：
Roger A Greenberg
金额：
$ 30.4万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8820272
关键词：
Address Androgen Receptor Antineoplastic Agents Ataxia-Telangiectasia-Mutated protein kinase BRCA1 gene BRCA2 gene Cancer Etiology Cell Death Cell Nucleus Chromatin Chromosomal Rearrangement Chromosomal translocation Chromosome abnormality Clinical Communication DNA Damage DNA Double Strand Break DNA Repair DNA Repair Gene DNA Sequence Rearrangement Data Double Strand Break Repair Event Gene Silencing Genetic Recombination Genetic Transcription Genome Genomic Instability Genomics Germ-Line Mutation Health Hematopoietic Hereditary Breast Carcinoma Histone H2A Human Hypersensitivity Imagery Immunologic Deficiency Syndromes Ionizing radiation Laboratories Location Lung Maintenance Malignant Neoplasms Malignant neoplasm of ovary Modality Movement Mutation Nuclear Observational Study Positioning Attribute Premature aging syndrome Prostate Publishing Radiobiology Reaction Reporting Site Stretching System Testing Thyroid Gland Time Transcription Alteration chemotherapy chromatin modification chromosome movement genome integrity insight interest novel novel strategies prevent response tumor

项目摘要

DESCRIPTION (provided by applicant): Gross chromosomal rearrangements are prominent in human cancers, with specific cytogenetic abnormalities contributing to hematopoietic, thyroid, prostate, and lung malignancies. Although the genesis of such chromosomal aberrations is incompletely understood, there is now strong evidence that a particularly dangerous situation arises when DNA double strand breaks (DSBs) occur in proximity to active transcription. These findings suggest that maintenance of genome integrity necessitates coordination between DNA repair and local transcriptional events. We have reported that DSBs silence transcription on contiguous stretches of chromatin in cis to DNA damage sites. Silencing requires ATM kinase activity and histone H2A ubiquitylation. We have extended these findings by discovering that DSB associated SUMOylation is essential for DSB silencing. An interesting observation from these studies is that ATM dependent DSB silencing prevents transcription dependent chromatin movement, a function that may relate to genome integrity control. This proposal utilizes several novel approaches to address two principle questions related to the interplay between DSB chromatin alterations and transcription: (i) How do DSB dependent chromatin alterations contribute to transcriptional gene silencing in cis to DSBs? (ii) Do DSB chromatin alterations promote accurate DNA repair mechanisms by opposing RNAPII driven chromatin movement? Collectively, these questions will address fundamental issues in genome integrity and radiation biology that are related to communication between DSB chromatin responses and transcription.

描述（由申请人提供）：人类癌症中突出染色体重排，特异性细胞遗传学异常有助于造血，甲状腺，前列腺和肺部恶性肿瘤。尽管这种染色体畸变的起源尚不完全理解，但现在有强有力的证据表明，当DNA双链断裂（DSB）发生在与主动转录附近时，会出现特别危险的情况。这些发现表明，维持基因组完整性需要在DNA修复和局部转录事件之间进行协调。我们报告说，DSBS在CIS中连续的染色质延伸到DNA损伤位点上的沉默转录。沉默需要ATM激酶活性和组蛋白H2A泛素化。我们通过发现与DSB相关的Sumoylation对DSB沉默至关重要，从而扩展了这些发现。从这些研究中的一个有趣的观察结果是，依赖于ATM的DSB沉默可以阻止转录依赖性染色质运动，该功能可能与基因组完整性控制有关。该建议利用几种新型方法来解决与DSB染色质改变和转录之间相互作用有关的两个主要问题：（i）DSB依赖性染色质的改变如何有助于CIS中的转录基因沉默到DSB中？（ii）DSB染色质的改变是否通过反对RNAPII驱动的染色质运动来促进准确的DNA修复机制？总的来说，这些问题将解决与DSB染色质反应和转录之间的交流有关的基因组完整性和辐射生物学中的基本问题。