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：
9001698
负责人：
Sudha Sharma
金额：
$ 32.7万
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 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9001698
关键词：
Age of Onset 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 Double Strand Break Repair Family Funding G-Quartets Gene Expression Gene Targeting Genes Genetic Transcription Genome Genome Stability Genomic Instability Genomics Goals Health Hereditary Disease Homeostasis Homologous Gene Human In Vitro Individual Knock-out Knowledge Link Maintenance Malignant Neoplasms Measures Modeling Molecular Molecular Analysis Mus Other Genetics Pathway interactions Patients Phenotype Predisposition Premature aging syndrome Productivity Proteins Publications Publishing RECQL4 gene RECQL5 gene Recombinant DNA Regulation Regulator Genes Replication Origin Reporting Research Role Rothmund-Thomson syndrome Structure System Telomere Maintenance Therapeutic Transcriptional Regulation 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 tumorigenic

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（由申请人证明）：RECQ解旋酶家族是一组高度caremes，被描述为基因组基因组的看护人。，RECQL5）与罕见的癌症易感性疾病有关（Werner综合征，Bloom综合征和Rothmund-Thomson综合征）。阐明特定RECQ蛋白的功能与疾病结局的功能受损是人类最丰富的RECQ同源物RECQ1的关系，这足以引起小鼠和人类细胞的不稳定性。在DNA链修复的机制中，基因组基因座在本质上很难形成次要结构。在这种更新应用中，我们假设RECQ1解旋酶促进了DNA修复的基因组机制，并通过特定的DNA识别DNA修复和转录调节。染色剂y REC调节的同源性背景中的转录组在RECQ功能中确定其重要性。探索可遗传疾病的特征对于发现如何揭示如何单个RECQ同源物在人类健康的背景下起作用。