权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
9548697
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 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9548697
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 Double Strand Break Repair Family Funding Gene Expression Genes Genetic Diseases Genetic Transcription Genome Genome Stability Genomic Instability Genomics Goals Health 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 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 rare cancer rare genetic disorder 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）功能丧失与罕见癌症易感性疾病（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。我们的目标是确定人类 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（包括癌症易感性和过早衰老）之间的关系。人类最丰富的 RecQ 同源物 RECQ1 的缺失足以导致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 与蛋白质的新相互作用，这些蛋白质支持 DNA 链断裂修复机制中的作用。此外，RECQ1 在本质上难以复制的基因组位点处富集，因为它们倾向于形成二级结构。包括 G4 DNA 在内的非 B DNA 结构可能对复制和转录提出挑战。 RECQ1 部分地通过与 G4 基序的特异性结合来改变基因表达，G4 基序预计会在体内靶基因启动子中形成 G4 DNA 结构。在此更新应用中，我们假设 RECQ1 解旋酶通过特定的蛋白质伴侣和对特殊 DNA 结构的识别，促进 DNA 修复和转录调控的基因组维护机制。我们的具体目标是：通过特定的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；并鉴定同基因背景中 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更详细地探索 RECQ1 在基因组维持中的具体作用及其在细胞稳态中更广泛的意义提供必要的框架。鉴于基因组维护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以及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。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Site-directed mutants of human RECQ1 reveal functional importance of the zinc binding domain.

人RECQ1的位置突变体揭示了锌结合结构域的功能重要性。

DOI：
10.1016/j.mrfmmm.2016.05.005
发表时间：
2016-08
期刊：
Mutation research
影响因子：
0
作者：
Sami F;Gary RK;Fang Y;Sharma S
通讯作者：
Sharma S

Long Noncoding RNA PURPL Suppresses Basal p53 Levels and Promotes Tumorigenicity in Colorectal Cancer.

长期非编码RNA PURPL抑制基础p53水平并促进大肠癌中的肿瘤性。

DOI：
10.1016/j.celrep.2017.08.041
发表时间：
2017-09-05
期刊：
Cell reports
影响因子：
8.8
作者：
Li XL;Subramanian M;Jones MF;Chaudhary R;Singh DK;Zong X;Gryder B;Sindri S;Mo M;Schetter A;Wen X;Parvathaneni S;Kazandjian D;Jenkins LM;Tang W;Elloumi F;Martindale JL;Huarte M;Zhu Y;Robles AI;Frier SM;Rigo F;Cam M;Ambs S;Sharma S;Harris CC;Dasso M;Prasanth KV;Lal A
通讯作者：
Lal A

Cellular deficiency of Werner syndrome protein or RECQ1 promotes genotoxic potential of hydroquinone and benzo[a]pyrene exposure.

沃纳综合征蛋白或 RECQ1 的细胞缺陷会促进氢醌和苯并[a]芘暴露的潜在遗传毒性。