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（由适用提供）：RECQ解旋酶家族是一组高度保守的DNA放松酶，称为基因组的看护人。在人类中，RECQ家族的五个成员（RECQ1，WRN，BLM，RECQL4和RECQL5）的功能丧失与罕见的癌症易感性疾病（Werner综合征，Bloom综合征和Rothmund-Thomson综合征）有关。我们的目标是确定人类RECQ解旋酶在基因组维持机制中的共同和专业功能。总体重点是阐明特定RECQ蛋白与疾病结局的功能受损，包括癌症的易感性和过早衰老。 RECQ1是人类中最丰富的RECQ同源物，足以在小鼠和人类细胞中引起基因组不稳定性。当前资金期间的工作确定了RECQ1与蛋白质的新型相互作用，这些蛋白质支持在DNA链破裂修复机理中的作用。此外，RECQ1在基因组部位上富集，由于其倾向O形成二级结构，因此本质上难以复制。包括G4 DNA在内的非B DNA结构可能对复制和转录构成挑战。 RECQ1通过其特异性结合与G4基序的特异性结合在体内形成G4 DNA结构，从而改变了基因表达。在这种续签应用中，我们假设RECQ1解旋酶通过特定的蛋白质伴侣以及对专用DNA结构的识别促进了DNA修复和转录调控的基因组维持机制。我们的具体目的是：通过特定的蛋白质伴侣和染色质相互作用来确定REC1在基因组维持中的作用；并在等源背景中识别RECQ调节的转录组，并确定其在RECQ函数中的重要性。通过拟议的研究获得的知识将为探索RECQ1在基因组维持中的特定作用及其在细胞体内稳态中更广泛的意义提供基本框架。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，因此了解特定RECQ蛋白的丧失如何促进基因组不稳定性和癌症易感性特征的可遗传性疾病的特征，这对于如何发现如何发现单个RECQ同源物在人类健康的背景下起作用。

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.

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.

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

A mutant p53/let-7i-axis-regulated gene network drives cell migration, invasion and metastasis.