Molecular Analysis of RECQ1 Functions in Genome Maintenance

RECQ1 在基因组维护中的功能的分子分析

• 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
• 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

 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(申请人提供)：RecQ解旋酶家族是一组高度保守的DNA解旋酶，被描述为基因组的管理者。在人类中，RecQ家族五个成员中的三个(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)存在遗传关联。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特殊功能。总体的重点是阐明特定RecQ蛋白的功能受损如何与疾病结局相关，包括癌症易感性和过早衰老。RECQ1是人类中含量最丰富的RecQ同源物，其缺失足以导致小鼠和人类细胞的基因组不稳定。在当前资助期的工作中发现了RECQ1与蛋白质的新相互作用，这些蛋白质支持在DNA链断裂修复机制中发挥作用。此外，RECQ1富含在基因组座位上，这些座位由于其形成二级结构的倾向而固有地难以复制。包括G4DNA在内的非B DNA结构可能对复制和转录都构成挑战。RECQ1部分通过与G4基序的特异性结合而改变基因表达，G4基序被预测在体内目标基因启动子中形成G4DNA结构。在这个更新应用中，我们假设RECQ1解旋酶通过特定的蛋白质伙伴和识别特定的DNA结构来促进DNA修复和转录调控的基因组维护机制。我们的具体目标是：通过特定的蛋白质配对和染色质相互作用，确定RECQ1在基因组维持中的作用；在等基因背景下识别RecQ调节的转录组，并确定其在RecQ功能中的意义。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内稳态中的更广泛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一种机制的重要性，了解特定的RecQ蛋白的丢失如何可能促进基因组的不稳定和它所导致的遗传病的癌症易感性特征，对于揭示其如何 单个RecQ同源基因在人类健康的背景下发挥作用。