Molecular Analysis of RECQ1 Functions in Genome Maintenance

RECQ1 在基因组维护中的功能的分子分析

基本信息

批准号：
9337461
负责人：
Sudha Sharma
金额：
$ 30.2万
依托单位：
HOWARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9337461
关键词：
Aging Aphidicolin Binding Bloom Syndrome CRISPR/Cas technology Cell Line Cells Characteristics Chromatin Chromosomal Breaks Chromosome Fragile Sites Complex DNA DNA Damage DNA Double Strand Break DNA Repair DNA Repair Gene DNA Structure DNA biosynthesis DNA replication fork DNA strand break Development Disease Disease Outcome Family Funding Gene Expression Gene Targeting Genes Genetic Transcription Genome Genome Stability Genomic Instability Genomics Goals Health Hereditary Disease Heritability Homeostasis Homologous Gene Human Impairment In Vitro Individual Inherited Knock-out Knowledge Link Maintenance Malignant Neoplasms Measures Modeling Molecular Molecular Analysis Mus Other Genetics Pathway interactions Patients Phenotype Predisposition Premature aging syndrome Productivity Professional Competence Proteins Publications Publishing RECQL4 gene RECQL5 gene Recombinant DNA Regulation Regulator Genes Replication Origin Reporting Research Role Rothmund-Thomson syndrome Small Interfering RNA Structure System Telomere Maintenance Therapeutic Transcriptional Regulation Tumorigenicity Werner Syndrome Work base cancer genetics helicase human disease in vivo insight loss of function loss of function mutation member novel premature prevent programs promoter public health relevance rRNA Precursor repaired telomere transcriptome tumor

项目摘要

DESCRIPTION (provided by applicant): The RecQ helicase family is a group of highly conserved DNA unwinding enzymes described as caretakers of the genome. In humans, loss of function of three of the five members of the RecQ family (RECQ1, WRN, BLM, RECQL4, and RECQL5) is genetically linked with rare cancer predisposition disease (Werner syndrome, Bloom syndrome, and Rothmund-Thomson syndrome). Our goal is to determine common and specialized functions of human RecQ helicases in mechanisms of genome maintenance. The overall focus is on elucidating how impaired function of a specific RecQ protein relates to disease outcomes, including cancer predisposition and premature aging. Loss of RECQ1, the most abundant RecQ homolog in humans, is sufficient to cause genomic instability in mouse and human cells. Work in current funding period identified novel interactions of RECQ1 with proteins that support a role in mechanisms of DNA strand break repair. Furthermore, RECQ1 was enriched at genomic loci that are intrinsically difficult to replicate due to their propensity o form secondary structures. Non-B DNA structures including G4 DNA may present challenges to both replication and transcription. RECQ1 alters gene expression, in part, through its specific binding with G4 motifs predicted to form G4 DNA structures in the target gene promoters in vivo. In this renewal application, we hypothesize that RECQ1 helicase facilitates genome maintenance mechanisms of DNA repair and transcriptional regulation through specific protein partners and recognition of specialized DNA structures. Our Specific Aims are: to determine the role of RECQ1 in genome maintenance through specific protein partners and chromatin interactions; and to identify RecQ-regulated transcriptome in isogenic background and determine its significance in RecQ functions. Knowledge gained through the proposed study will provide essential framework for exploring in more detail the specific roles of RECQ1 in genome maintenance and its broader significance in cellular homeostasis. Given the importance of genome maintenance as a mechanism to prevent cancer and other genetic diseases, understanding how the loss of a specific RecQ protein may promote genomic instability and cancer susceptibility characteristic of the heritable disease it causes is essential to uncover how individual RecQ homologs work in context of the human health.

描述（由申请人提供）：RecQ 解旋酶家族是一组高度保守的 DNA 解旋酶，被描述为基因组的守护者。在人类中，RecQ 家族五个成员中的三个（RECQ1、WRN、BLM、 RECQL4 和 RECQL5）与罕见的癌症易感性疾病（沃纳综合征、布卢姆综合征和罗斯蒙德-汤姆森综合征）存在遗传相关性。确定人类 RecQ 解旋酶在基因组维持机制中的常见和特殊功能，总体重点是阐明特定 RecQ 蛋白功能受损与疾病结果的关系，包括癌症易感性和最丰富的 RecQ 同源物 RECQ1 的缺失。在人类中，足以引起小鼠和人类细胞的基因组不稳定。当前资助期间的工作发现了 RECQ1 与支持 DNA 链断裂修复机制的蛋白质的新相互作用。由于其倾向于形成非 B DNA 结构（包括 G4 DNA），RECQ1 可能在一定程度上通过与 G4 基序的特异性结合来改变基因表达。预测在体内靶基因启动子中形成 G4 DNA 结构在这项更新应用中，我们研究了 RECQ1 解旋酶通过特定的蛋白质伙伴和特定 DNA 结构的识别来促进 DNA 修复和转录调控的基因组维持机制。目的是：通过特定蛋白质伙伴和染色质相互作用确定 RECQ1 在基因组维护中的作用；并在同基因背景中识别 RecQ 调节的转录组并确定其在 RecQ 功能中的重要性通过拟议的研究获得的知识将为探索提供必要的框架。更详细地了解 RECQ1 在基因组维持中的具体作用及其在细胞稳态中的更广泛意义鉴于基因组维持作为预防癌症和其他遗传疾病的机制的重要性，了解特定 RecQ 蛋白的丢失如何促进基因组不稳定。其引起的遗传性疾病的癌症易感性特征对于揭示其如何发生至关重要各个 RecQ 同源物在人类健康的背景下发挥作用。