Regulation of rRNA Genes by Silencing Mechanisms

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重复核糖体RNA （rRNA）基因的稳定性。该位点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重复以对抗同源重组的机制提供了机会。我们已经确定了调节rDNA重组的沉默复合物。这些复合物的分子组成提示了一种新的机制，即如何在重复的DMA区域内减少同源重组。该机制可能涉及到在DMA复制后，姐妹DNA染色单体通过称为高铁蛋白复合物的夹紧复合物桥接，防止DNA重复相对滑动。这种夹紧抑制了注册外重复单元之间不适当的重组事件。第二组蛋白质位于核膜内，并与高铁蛋白发生物理相互作用。这些膜蛋白可能将rRNA基因拴在核外周。提出这种绑定是为了提供防止不适当重组的第二种保障。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的一般染色体不稳定性有关。对酵母中确保DNA重复序列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序列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来处理染色体稳定性疾病。

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.