RIBOSOMAL GENES OF YEAST AND THEIR REGULATION

在酿酒酵母的生长细胞中，核糖体蛋白基因的转录占RNA聚合酶II起始事件的30%。 此外，细胞以等摩尔量产生核糖体的80种组分。 因此，核糖体的合成不仅需要消耗细胞资源的主要部分，而且还需要精细的控制以避免组分之间的不平衡。 核糖体的产生不仅受营养来源和其他外部因素的调节，而且还受整合细胞操作的细胞内信号转导途径的调节。 这种整合是显而易见的，从我们的观察，任何缺陷的分泌途径，负责膜的合成，导致核糖体RNA和核糖体蛋白质基因的合成的快速抑制。我们建议沿着沿着两条互锁的路线研究这种调节的分子基础。 (I)我们将尝试识别137个核糖体蛋白基因中每一个的“签名”，（a）通过诱变、嵌合启动子等，(b)通过鉴定阻遏物激活蛋白Rap1p的这种调节的活性位点，（c）通过使用全基因组表达测定来鉴定任何“异常”的核糖体蛋白基因，即，与其他基因协调调控，而其他基因组可能与核糖体蛋白协调调控。 (II)我们将建立一个遗传筛选，以确定不再抑制核糖体合成的突变体，以响应分泌途径中的缺陷，希望确定参与者（a）在检测缺陷，（B）在信号转导途径，通知细胞核，和（c）在转录装置，响应该通知。由于生长依赖于蛋白质的合成，而蛋白质的合成又依赖于核糖体的合成，因此控制核糖体的合成就真实的导致了对生长的控制。 细胞生长的不平衡是许多疾病的原因。 我们的希望和期望是，了解核糖体合成调节的基础电路将在失衡发生时进行更有效的干预。

In a growing cell of Saccharomyces cerevisiae transcription of the ribosomal protein genes makes up 30 percent of the RNA polymerase II initiation events. Furthermore, the cell produces the 80 components of the ribosome in equimolar amounts. Thus, the synthesis of ribosomes requires not only the consumption of a major portion of the cell's resources, but also the delicate control necessary to avoid imbalance among the components. The production of ribosomes is regulated not only by the source of nutrients and other external factors, but also by intracellular signal transduction pathways that integrate the operations of the cell. This integration is evident from our observation that any defect in the secretory pathway, responsible for the synthesis of membranes, leads to a rapid repression of the synthesis of both ribosomal RNA and ribosomal protein genes. We propose to investigate the molecular basis of this regulation along two interlocking lines. (I) We will try to identify the 'signature' that identifies each of the 137 ribosomal protein genes, (a) through mutagenesis, chimeric promoters, etc., (b) by identifying the active sites, for this regulation, of the repressor activator protein Rap1p, (c) by using genome-wide expression assays to identify any ribosomal protein gene that is an 'outlier', i.e., is not coordinately regulated coordinately with the others, and for other sets of genes that might be regulated coordinately with the ribosomal proteins. (II) We will set up a genetic screen to identify mutants that no longer repress ribosome synthesis in response to a defect in the secretory pathway, hoping to identify participants (a) in the detection of the defect, (b) in the signal transduction pathway that notifies the nucleus, and (c) in the transcriptional apparatus that responds to that notification. Since growth depends on protein synthesis and protein synthesis depends on ribosome synthesis, the control of ribosome synthesis leads, in a very real sense, to the control of growth. Imbalance in the growth of cells is the cause of much disease. Our hope, and expectation, is that understanding the circuits that underlie the regulation of ribosome synthesis will lead to more effective intervention when an imbalance occurs.