DNA helicase functions in genome maintenance

DNA 解旋酶在基因组维护中的功能

基本信息

批准号：
8689253
负责人：
ROBERT SKIBBENS
金额：
$ 34.98万
依托单位：
LEHIGH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8689253
关键词：
Acetylation Acetyltransferase Address Aneuploidy Apoptosis Apoptotic Architecture Binding Biochemical Bruck-de Lange syndrome Cell Cycle Cells Chromatin Chromatin Structure Chromosome Condensation Cleft Palate Clinical Complex Congenital Abnormality Congenital Heart Defects DNA DNA Structure DNA biosynthesis Defect Deposition Development Disease Exhibits Face Failure Family Gap Junctions Genes Genetic Genetic Transcription Genital system Genome Genomic Instability Goals Growth Hearing Heart Human Impaired cognition Impairment Intellectual functioning disability Kidney Limb structure Link Maintenance Malignant Neoplasms Metabolism Methodology Methods Microcephaly Mitotic Modeling Molecular Molecular Genetics Mutate Mutation Nature Outcome Pathway interactions Penetrance Phenotype Proteins Reaction Recruitment Activity Regulation Research Proposals Resolution Roberts-SC phocomelia syndrome Role S Phase Saccharomycetales Severities Signal Transduction Sister Chromatid Site Stem cells Structure Syndrome Testing Vision Yeast Model System base cancer cell cognitive function cohesin cohesion deafness developmental disease helicase insight mutant novel public health relevance research study response

项目摘要

DESCRIPTION (provided by applicant): Cohesion factor mutations are firmly situated at the nexus of birth defects, severe cognitive impairment, cell aneuploidy and cancer. Presently, mutations within different classes of cohesion factors (cohesin tethers, deposition complex and establishment factors) are thought to result in different developmental maladies: cohesin and deposition mutations give rise to Cornelia de Lange Syndrome (CdLS) while establishment mutations give rise to Roberts Syndrome (RBS). The molecular bases for these birth defects are also considered to be separate, despite the very similar nature of these multispectrum maladies: CdLS arising from transcription dysregulation, RBS arising from apoptotic loss of progenitor cells. We first identified and now have characterized a third class of cohesion factors - Chl1 DNA helicase. Mutations in human Chl1 (ChlR1/DDX11) leads to another multispectrum developmental disorder, termed Warsaw Breakage Syndrome (WABS) that share many features (cognitive impairment, cranio/facial abnormalities, growth retardation, deafness, heart defects and extremity impairments) found in both CdLS and RBS. In the course of our studies, we found that Chl1 both interacts with establishment factor Eco1 and is required for the recruitment to DNA of both cohesin and cohesin deposition complex. From this, we hypothesize that WABS, CdLS and RBS are in reality a single disease state differentiated only by penetrance and severity. Currently, Chl1 DNA helicase is uniquely placed as the founding link through which all three maladies can be studied in the aggregate. Despite the critical (and clinical) nature of Chl1, little is known regarding its regulation, site of action or impact on chromatin architecture. In this proposal, we use genetic, molecular and biochemical methodologies to exploit Chl1 in the budding yeast model system to address fundamental questions of conserved pathways relevant to both birth defects and aneuploidy in humans. Specifically, we propose to elucidate the mechanism through which Chl1 is recruited to DNA specifically during DNA replication (Specific Aim1) and identify the mechanism through which Chl1 promotes cohesin deposition activity, focusing on chromatin architecture (Specific Aim 2)

描述（由申请人提供）：内聚力因子突变牢固地位于先天缺陷，严重的认知障碍，细胞非整倍性和癌症的联系。目前，认为不同类别的凝聚因子（凝聚素tethers，沉积复合物和建立因子）中的突变被认为会导致不同的发育疾病：凝聚蛋白和沉积突变会导致Cornelia de Lange综合征（CDLS），而建立突变引起了罗伯茨综合征（RBS）。尽管这些多光谱疾病的性质非常相似，但这些先天缺陷的分子碱基也被认为是分开的：CDL是由转录失调引起的，RB是由祖细胞的凋亡损失引起的。我们首先确定并现在表征了第三类内聚力因子-CHL1 DNA解旋酶。人CHL1（CHLR1/DDX11）的突变导致另一种多光谱发育障碍，称为Warsaw Breakage综合征（WABS），它们具有许多特征（认知障碍，Cranio/cranio/cranio/cranio/cranio/cranio/cranio/cranio normality，成长智慧，障碍，聋哑，心脏缺陷，心脏缺陷和极端障碍），在CDLS中都发现了。在我们的研究过程中，我们发现CHL1都与建立因子ECO1相互作用，并且是募集到粘着蛋白和粘着蛋白沉积复合物DNA所必需的。由此，我们假设WAB，CDLS和RBS实际上是一种单一的疾病状态，仅由外渗和严重程度与众不同。目前，CHL1 DNA解旋酶是独特的，作为创始链接，可以通过该链接在骨料中研究所有三个疾病。尽管CHL1具有至关重要的（和临床）性质，但关于其调节，作用部位或对染色质结构的影响知之甚少。在此提案中，我们使用遗传，分子和生化方法学来利用萌芽的酵母模型系统中的CHL1来解决与人类先天缺陷和非整倍性相关的保守途径的基本问题。具体而言，我们建议阐明在DNA复制过程中募集CHL1的机制（特定AIM1），并确定CHL1促进粘蛋白沉积活性的机制，重点是染色质构建（特定目标2）