ATR-Chk1 signaling during embryonic and germ line development in C. elegans

秀丽隐杆线虫胚胎和种系发育过程中的 ATR-Chk1 信号传导

基本信息

批准号：
8610930
负责人：
MATTHEW MICHAEL
金额：
$ 31.22万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-01 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8610930
关键词：
ATM Signaling Pathway ATM activation ATM function Address Animal Model Animals Biochemical Biological Assay Biology Caenorhabditis elegans Cancer Biology Cancerous Cell Cycle Cell Cycle Arrest Cell Cycle Progression Cell Cycle Regulation Cell Death Cell Line Cell Proliferation Cell division Cells Chromosomes Complex Cultured Cells DNA Damage DNA Repair Pathway DNA biosynthesis Data Development Embryo Embryonic Development Eukaryotic Cell Event Failure Fission Yeast Foundations Future Generations Genome Genome Stability Germ Cells Germ Lines Goals Human KRP protein Knowledge Laboratories Larva Maintenance Mitosis Molecular Monitor Motion Mutation Nematoda Organism Pathway interactions Phosphatidylinositols Play Population Process Prophase Protein Kinase Protein-Serine-Threonine Kinases Proteins Proteomics RNA Interference Rana Regulation Relative (related person)Reproduction Role S Phase Saccharomycetales Signal Pathway Signal Transduction Signal Transduction Pathway Specificity Stem cells Sterility Stress Structure Structure of primordial sex cell System TREX1 gene Testing Time Work attenuation base biological adaptation to stress cell type egg embryo stage 2 feeding functional genomics genetic analysis hatching human stem cells human tissue insight killings novel positional cloning prevent programs reproductive research study response tissue culture

项目摘要

DESCRIPTION (provided by applicant): The ATR-Chk1 signaling pathway plays crucial roles in cell cycle control and in the cellular response to replication stress. The mechanistic basis for ATR-Chk1 function is beginning to be understood, thanks largely to intensive study of the pathway in homogenous populations of human tissue culture cells, or simpler organisms such as budding and fission yeasts. Less well understood are the pathway's function(s) in the development and reproduction of animals, and thus to gain a deeper understanding of more specialized functions of this pathway, ATR-Chk1 will be investigated in the metazoan roundworm C. elegans. During C. elegans embryogenesis, ATR-Chk1 controls the timing of cell division in a lineage-specific manner. Preliminary data in support of this application suggest that activation of the ATR-Chk1 pathway during embryogenesis occurs via a different mechanism than has been described in other systems, and thus the goal of Aim 1 is to identify ATR activators and to study the activation mechanism. Aim 2 seeks to understand the basis for lineage-specific signaling of ATR-Chk1 during embryogenesis. Aim 3 examines a novel function for ATR- Chk1, in cell cycle re-entry after long-term arrest in germ line stem cells. During germ line development in C. elegans, the stem cells Z2 and Z3 arrest the cell cycle at prophase, and these cells remain arrested until the larva hatches and begins to feed. Preliminary data in support of this application demonstrate that Chk1 plays a crucial role during the cell cycle re-entry process. Attenuation of Chk1 activity perturbs the timing of reentry, causes DNA damage, and ultimately kills these germ line stem cells, rendering the animal sterile. The goal of Aim 3 is thus to uncover the molecular basis for this novel function of Chk1. Successful completion of the work proposed in this application will significantly broaden our understanding of ATR-Chk1 function during embryonic and germ line development. These experiments will also provide insight into how basic cell cycle processes are integrated with developmental and reproductive events. Finally, insight into ATR-Chk1 function during human stem cell proliferation will likely result from completion of this work, as it is well established that the basic mechanism of asymmetric cell division is highly conserved throughout metazoans.

描述（由申请人提供）：ATR-CHK1信号通路在细胞周期控制以及对复制应力的细胞反应中起着至关重要的作用。 ATR-CHK1功能的机理基础开始被理解，这在很大程度上要归功于对人类组织培养细胞同质种群的途径的深入研究，或者是更简单的生物，例如萌芽和裂变酵母。不太了解的是途径在动物的开发和繁殖中的功能，因此为了更深入地了解该途径的更专业功能，将在Metazoan round虫C.秀隐杆线虫中研究ATR-CHK1。在秀丽隐杆线虫的胚胎发生过程中，ATR-CHK1以谱系特异性方式控制细胞分裂的时间。支持该应用的初步数据表明，胚胎发生过程中ATR-CHK1途径的激活是通过与其他系统中描述的不同机制发生的，因此AIM 1的目的是识别ATR激活剂并研究激活机制。 AIM 2试图了解胚胎发生过程中ATR-CHK1的谱系特异性信号的基础。 AIM 3检查了在生殖系干细胞长期停止后，在细胞周期重新进入ATTR-CHK1的新功能。在秀丽隐杆线虫的生殖线发育过程中，干细胞Z2和Z3阻止了预言的细胞周期，并且这些细胞一直被捕，直到幼虫孵化并开始进食。支持此应用的初步数据表明，CHK1在细胞周期重新进入过程中起着至关重要的作用。 CHK1活性的衰减会导致再入的时间，导致DNA损伤，并最终杀死这些生殖系干细胞，从而使动物无菌。因此，目标3的目的是揭示CHK1新功能的分子基础。成功完成本应用程序中提出的工作将大大扩大我们对胚胎和种系开发过程中ATR-CHK1功能的理解。这些实验还将提供有关基本细胞周期过程如何与发育和生殖事件集成的见解。最后，在人类干细胞增殖过程中对ATR-CHK1功能的洞察力可能是由于完成这项工作而引起的，因为可以很好地确定，不对称细胞分裂的基本机制在整个后生动物中都高度保守。