Regulation of G1-specific gene expression in yeast

酵母中 G1 特异性基因表达的调控

• 批准号: 7892243
• 负责人: CURT WITTENBERG
• 金额: $ 41.04万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-13 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7892243
• 关键词: Amino Acid Sequence; Binding; Cell Cycle; Cell Cycle Checkpoint; Cell Cycle Progression; Cell Cycle Regulation; Cell Proliferation; Cell Proliferation Regulation; Cell Size; Cells; DNA Repair; DNA Structure; DNA biosynthesis; DNA damage checkpoint; Enzymes; Eukaryota; Event; Family; Family member; Fission Yeast; G1 Phase; Gap Junctions; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Genome Stability; Goals; Homologous Gene; Human; Human Biology; Malignant Neoplasms; Medicine; Nature; Nucleotides; Organism; Phosphorylation; Play; Process; Protein Kinase; Proteins; Regulation; Research; Role; Saccharomyces cerevisiae; Saccharomycetales; Signal Pathway; Signal Transduction; System; Testing; Transcription Repressor/Corepressor; Transcriptional Regulation; Yeasts; base; human DNA; insight; man; novel; numb protein; programs; repaired; research study; response; transcription factor

DESCRIPTION (provided by applicant): The capacity to faithfully replicate is one of the hallmarks of living systems. The overall goal of our research program is to understand the control of cell proliferation in eukaryotes. That regulation is imposed during G1 phase of the cell cycle via the regulation of the expression of a large family of G1- specific genes. We have previously described two novel repressors of G1-specific gene expression in yeast. Whi5 binds and represses SBF, one of two G1-specific transcription factors, during early G1 phase whereas Nrm1 acts as a co-repressor with MBF to repress G1 specific transcription as cells exit G1 phase. Both regulators play critical roles in cell cycle checkpoints that impose order on cell cycle events: Whi5 in the G1 cell size checkpoint and Nrm1 in the DNA replication checkpoint. The application is presented in three specific aims. First, we propose to characterize the role of Swi6, a shared component of MBF and SBF, as a platform for regulation of transcription by studying the basis for its interaction with Whi5 and Nrm1 and the regulation of that interaction by protein phosphorylation. Second, we propose to determine the mechanism and role of control of MBF regulated transcription by the DNA replication checkpoint. Nrm1 acts at the nexus between the checkpoint signaling pathway and the cell cycle machinery. The checkpoint regulates the Nrm1/MBF interaction via phosphorylation by checkpoint protein kinases and is important for genomic stability. Third, we propose to establish the role of the RAK motif, an amino acid sequence motif conserved between Nrm1, Whi5 and other proteins that defines a Nrm1/Whi5 superfamily. We expect that this amino acid sequence conservation belies a conserved aspect of cell cycle regulation by those proteins. We anticipate that completion of these specific aims will provide a broader understanding of the regulation of G1-specific transcription both during the cell cycle and in response to activation of the DNA replication checkpoint. Understanding this mechanism in the distantly related budding yeast, Saccharomyces cerevisiae, and fission yeast, Schizosaccharomyces pombe, promises to establish paradigms to be tested in the context of the regulation of cell proliferation and the human DNA replication checkpoint response. Misregulation of both of those processes has been associated with human cancer. We are hopeful that a more general view of the cell cycle-regulated transcriptional machinery and its regulators will offer insight into human biology and medicine.

描述（由申请人提供）：忠实复制的能力是生活系统的标志之一。我们研究计划的总体目标是了解真核生物中细胞增殖的控制。该调节是通过调节大型G1-特异性基因的表达在细胞周期的G1阶段施加的。我们先前已经描述了酵母中G1特异性基因表达的两个新型抑制剂。 WHI5在G1早期结合并抑制SBF，这是两个G1特异性转录因子之一之一，而NRM1充当了与MBF的共抑制剂，以抑制G1特异性转录作为细胞退出G1相。两个调节器都在细胞周期检查点上扮演关键的作用，该检查点对细胞周期事件施加顺序：G1单元大小检查点中的WHI5和DNA复制检查点中的NRM1。该应用程序以三个具体目标呈现。首先，我们建议通过研究与WHI5和NRM1相互作用的基础以及通过蛋白质磷酸化来调节这种相互作用的基础，以表征SWI6（MBF和SBF共享组成部分）的作用。其次，我们建议通过DNA复制检查点确定MBF调节转录的控制的机理和作用。 NRM1在检查点信号通路和细胞周期机械之间的NRM1作用。检查点通过检查点蛋白激酶通过磷酸化来调节NRM1/MBF相互作用，对于基因组稳定性很重要。第三，我们建议建立RAK基序的作用，RAK基序是NRM1，WHI5和其他定义NRM1/WHI5超家族的氨基酸序列基序。我们预计这种氨基酸序列保护掩盖了这些蛋白质细胞周期调节的保守方面。我们预计，这些特定目标的完成将为细胞周期中G1特异性转录的调节提供更广泛的了解，并响应于激活 DNA复制检查点。了解这种机制在遥远相关的酵母中，酿酒酵母和裂变酵母，schizosacchomyces pombe有望建立 在细胞增殖和人DNA的调控背景下要测试的范例 复制检查点响应。这两个过程的不正体都与 人类癌。我们希望对细胞周期调节的转录更一般的看法 机械及其监管机构将提供有关人类生物学和医学的见解。