Regulation of rRNA Genes by Silencing Mechanisms

沉默机制对 rRNA 基因的调控

• 批准号: 7354793
• 负责人: DANESH MOAZED
• 金额: $ 24.17万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7354793
• 关键词: Adaptor Signaling Protein; Affinity Chromatography; Binding; Biochemistry; Cell Nucleolus; Cells; Chromatids; Chromatin Structure; Chromosomal Instability; Chromosomal Stability; Chromosome Structures; Complex; DNA; DNA Maintenance; DNA Sequence; Deacetylation; Disease; Ensure; Eukaryota; Eukaryotic Cell; Event; Gene Silencing; Genetic Recombination; Genetic Transcription; Genome; Goals; Growth; Human; In Vitro; Integral Membrane Protein; Laboratories; Lead; Link; Localized; Maintenance; Malignant Neoplasms; Mass Spectrum Analysis; Meiotic Recombination; Membrane Proteins; Mitosis; Mitotic; Molecular; Nature; Nuclear; Nuclear Envelope; Nuclear Protein; Nuclear Proteins; Protein Analysis; Protein phosphatase; Proteins; Proteomics; RNA Polymerase II; Recombinant DNA; Regulation; Relative (related person); Research Personnel; Ribosomal DNA; Role; Saccharomyces cerevisiae; Saccharomycetales; Set protein; Sister; Sister Chromatid; Slide; Testing; Therapeutic; Work; Yeasts; cohesin; cohesion; design; env Gene Products; homologous recombination; in vivo; insight; prevent; programs; promoter; protein protein interaction; rRNA Genes; role model; stoichiometry

DESCRIPTION (provided by applicant): The long-term goal of this work is to understand how gene silencing mechanisms regulate the stability of the highly repetitive ribosomal RNA (rRNA) genes. The stability of this locus is crucial for growth and survival and its highly repetitive nature presents an opportunity to explore the mechanisms that stabilize DNA repeats against homologous recombination. We have identified the silencing complexes that regulate rDNA recombination. The molecular composition of these complexes suggests a new mechanism for how homologous recombination within repetitive DMA regions can be curtailed. The mechanism is likely to involve the bridging of sister DNA chromatids after DMA replication by a clamp complex, termed the cohibin complex, that prevents DNA repeats from sliding relative to each other. This clamping inhibits inappropriate recombination events between out of reguster repeat units. A second set of proteins is localized to the inner nuclear envelop and physically interacts with cohibin. These membrane proteins may tether rRNA genes to the nuclear periphery. This tethering is proposed to provide a second safeguard against inappropriate recombination. Repeated DNA sequences form the largest portion of the genomes of complex eukaryotes such as humans. Repeat instability is associated with general chromosome instability in cancers and other diseases. A basic understanding of the mechanisms that ensure the stability of DNA repeats in yeast will also increase our understanding of repeat and chromosome stability in human cells and may lead to the design of better preventative and therapeutic strategies that deal with diseases of chromosome stability.

描述(申请人提供)：这项工作的长期目标是了解基因沉默机制如何调节高度重复的核糖体RNA(RRNA)基因的稳定性。该基因座的稳定性对生长和生存至关重要，其高度重复的性质为探索稳定DNA重复对抗同源重组的机制提供了机会。我们已经确定了调节rDNA重组的沉默复合体。这些复合体的分子组成表明了一种新的机制，即如何减少重复DMA区域内的同源重组。这种机制可能涉及到在DMA复制后，姐妹DNA染色单体之间通过一种名为cohibin复合体的钳制复合体桥接，该复合体防止DNA重复序列相对于彼此滑动。这种钳制抑制了调控外重复单元之间的不适当重组事件。第二组蛋白质定位于内核膜，并与Cohibin物理上相互作用。这些膜蛋白可能将rRNA基因拴在核周。这种系留是为了提供第二种防止不适当重组的保护措施。重复的DNA序列构成了人类等复杂真核生物基因组的最大部分。重复不稳定与癌症和其他疾病中普遍存在的染色体不稳定有关。对确保酵母中DNA重复序列稳定性的机制的基本了解也将增加我们对重复序列和人类细胞中染色体稳定性的理解，并可能导致设计出更好的预防和治疗策略，以处理染色体稳定性疾病。