Cell Progression Through Meiosis: A Signal From Recombination to the First Division

减数分裂的细胞进展：从重组到第一次分裂的信号

• 批准号: 0416956
• 负责人: Robert Malone
• 金额: $ 15万
• 依托单位: University of Iowa
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-15 至 2006-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0416956&HistoricalAwards=false
• 关键词: Cell; Progression; Through; Meiosis; Signal

Meiosis is the highly conserved, special cell division process in which gametes are made. At the chromosome level, "premeiotic" DNA synthesis, recombination and synapsis, the reductional division, the equational division, and packaging (into sperm, spores, etc.) all must be coordinated and occur in the right order and time. The long-range goal of this research is the understanding of chromosome behavior in meiosis and the focus of this project is the understanding of the communication between two steps unique to, and essential for, meiosis: recombination and the first (MI) meiotic chromosome division. Using the yeast S. cerevisiae, the investigator has defined a mode of communication in meiosis that occurs in normal cells; he refers to this as the "recombination initiation signal" (RIS) because it requires gene products that initiate recombination. The normal outcome of the RIS in wild type (WT) cells is to delay the MI division to allow time for recombination to proceed; mutants lacking the signal begin the MI division at an earlier time. During the current NSF grant, the investigator has shown that the meiotic RIS requires the recombination initiation genes REC102, REC104, MER2/REC107, REC114, SPO11, and RAD50 (but not MEI4 or REC103/SKI8) and the synaptonemal complex genes HOP1 and RED1. The RIS is not a traditional checkpoint that arrests mutant/defective cells: it is WT cells that have the delay. During the year of funding the laboratory will focus on two areas. First they will examine the mechanism of how the RIS is transduced to delay the MI division. They have discovered that the mitotic DNA damage checkpoint (although important for a late recombination checkpoint) is not involved in transducing the RIS. They will test two other well-studied checkpoints, the DNA synthesis checkpoint and the spindle checkpoint, to determine if they have a role in the RIS. The second aim of the research is to determine how the target of the RIS (the meiotic transcriptional activator NDT80) is affected. They have demonstrated that NDT80 transcription is increased and active protein is produced at earlier times in the absence of the RIS. To understand the mechanism of the normal RIS delay which occurs in WT cells, they will examine the upstream regulators and posttranslational modifiers of this regulator to determine which of them respond to the RIS. The combination of these two approaches will help to define how recombination is coordinated with the reductional division during meiosis.The investigator is actively involved in teaching undergraduate and graduate students both the critical thinking necessary to design experiments to advance our understanding of natural biological processes and the techniques to carry them out. Through this project the investigator should produce valuable scientific insights and thoughtful, well-trained researchers.

减数分裂是一种高度保守的、特殊的细胞分裂过程，在这个过程中产生配子。在染色体水平上，“减数分裂前”DNA的合成、重组和突触、还原分裂、等速分裂和包装（形成精子、孢子等）都必须协调一致，并按正确的顺序和时间发生。本研究的长期目标是了解染色体在减数分裂中的行为，本项目的重点是了解减数分裂中独特且必不可少的两个步骤：重组和第一次减数分裂染色体分裂之间的交流。利用酿酒酵母，研究者定义了正常细胞减数分裂中的一种通讯模式；他将其称为“重组启动信号”（RIS），因为它需要启动重组的基因产物。RIS在野生型（WT）细胞中的正常结果是延迟心肌分裂，以便有时间进行重组；缺乏信号的突变体在更早的时间开始心肌分裂。在目前的NSF资助期间，研究者已经证明减数分裂RIS需要重组起始基因REC102、REC104、MER2/REC107、REC114、SPO11和RAD50（但不需要MEI4或REC103/SKI8）和突触复合体基因HOP1和RED1。RIS不是捕获突变/缺陷细胞的传统检查点：它是具有延迟的WT细胞。在资助期内，实验室将重点关注两个领域。首先，他们将研究RIS如何被转导延缓心肌分裂的机制。他们发现有丝分裂DNA损伤检查点（尽管对晚期重组检查点很重要）不参与RIS的转导。他们将测试另外两个被充分研究过的检查点，DNA合成检查点和纺锤体检查点，以确定它们是否在RIS中起作用。该研究的第二个目的是确定RIS（减数分裂转录激活因子NDT80）的靶标是如何受到影响的。他们已经证明，在没有RIS的情况下，NDT80的转录增加，活性蛋白在更早的时间产生。为了了解发生在WT细胞中的正常RIS延迟的机制，他们将检查上游调节因子和该调节因子的翻译后修饰因子，以确定哪些调节因子对RIS有反应。这两种方法的结合将有助于确定减数分裂过程中重组是如何与减数分裂协调的。研究者积极参与教授本科生和研究生设计实验所需的批判性思维，以提高我们对自然生物过程的理解，以及实施实验的技术。通过这个项目，研究者应该产生有价值的科学见解和有思想的、训练有素的研究人员。