Regulation of rRNA Genes by Silencing Mechanisms

沉默机制对 rRNA 基因的调控

基本信息

批准号：
8006014
负责人：
DANESH MOAZED
金额：
$ 9.35万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-08 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8006014
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 Event Gene Silencing Genetic Recombination Genetic Transcription Genome Goals Growth Human In Vitro Integral Membrane Protein Laboratories Lead Link 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 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

项目摘要

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（由申请人提供）：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于生长和生存至关重要，其高度重复的性质为探索稳定DNA重复反对同源重组的机制提供了机会。我们已经确定了调节rDNA重组的沉默复合物。这些复合物的分子组成提出了一种新的机制，即如何减少重复性DMA区域中的同源重组。该机制可能涉及通过称为cohibin复合物的夹子复制后姊妹DNA染色单体的桥接，从而防止DNA重复相对于彼此的滑动。这种夹具抑制了复发重复单元之间不适当的重组事件。第二组蛋白质定位于内部核包膜，并与Cohibin物理相互作用。这些膜蛋白可能会将rRNA基因绑定到核周围。提议这种束缚为防止不适当重组提供第二种保障措施。重复的DNA序列构成了复杂真核生物（如人类）基因组的最大部分。重复不稳定性与癌症和其他疾病中的一般染色体不稳定性有关。对确保酵母中DNA重复稳定性的机制的基本理解也将增加我们对人类细胞中重复和染色体稳定性的理解，并可能导致设计更好的预防和治疗策略，以处理处理染色体稳定性疾病的疾病。