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Cell Cycle Checkpoint in Response to DNA Damage

DNA 损伤反应中的细胞周期检查点

基本信息

批准号：
7260492
负责人：
NANCY C WALWORTH
金额：
$ 38.89万
依托单位：
UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-08-01 至 2008-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7260492
关键词：
ATM gene Alleles Apoptosis Ataxia Telangiectasia Binding Biochemical Biochemical Genetics Biological Models Breast Cancer Cell C-terminal Categories Cell Cycle Cell Cycle Arrest Cell Cycle Checkpoint Cell Cycle Progression Cell Cycle Regulation Cell Death Cells Checkpoint kinase 1 Chromatin Chromosomes DNA DNA Damage DNA Replication Damage DNA damage checkpoint Detection Disruption Ensure Eukaryota Eukaryotic Cell Event Exhibits Exposure to Fission Yeast Frequencies Genes Genetic Genome Genome Stability Goals Hereditary Disease Histone Deacetylase Inhibitor Histone H3 Histones Homologous Gene Human Immunodeficiency and Cancer Incidence KDM5B gene Lead Malignant Neoplasms Mammalian Cell Mediating Mitosis Modification Mutation PHD Finger PLU-1 gene Pathway interactions Pharmaceutical Preparations Phosphorylation Phosphorylation Site Play Population Protein Kinase Proteins Rate Research Personnel Risk Role Schizosaccharomyces pombe Proteins Sequence Homology Signal Transduction Pathway Site Substrate Domain System Testing Time Tumor Suppressor Proteins Yeasts base cell type coping design insight loss of function mutant novel programs progressive neurodegeneration protein function research study response segregation ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): Cell cycle checkpoints ensure the integrity of the genome from one replicative cell cycle to the next. In the event of catastrophic damage to the genome, cells of multicellular eukaryotes can undergo apoptosis, presumably to eliminate them from the cell population and reduce the risk of propagating genetically unstable cells. Alternatively, cells may respond to DNA damage by undergoing a transient arrest of the cell cycle, which correlates with their ability to survive exposure to DNA damaging agents. This response requires the DNA damage checkpoint pathway; if compromised by mutation or drug treatment, cells will enter mitosis with damaged DNA and die. The fission yeast has been an extremely valuable system for identifying and characterizing components of the DNA damage checkpoint. Indeed, many proteins that are now known to function in the checkpoint pathway in mammalian cells were identified solely based on their sequence homology to proteins that were identified genetically and functionally in yeast. Thus, it is clear that the identification of proteins in yeast using the power of classical genetics is a valid and productive means of identifying and gaining insight into the function of mammalian counterparts. Experiments described in this proposal will continue to investigate the protein kinase, Chk1, a key regulator of the checkpoint in eukaryotic cells. In addition, we will focus on a novel fission yeast protein, Msc1. Msc1 shares structural domain homology with mammalian RbBP2, a protein identified by virtue of its ability to bind the tumor suppressor protein Rb and with PLU-1, the product of a gene that is up regulated in breast cancer cells. Msc1 was cloned because it can compensate for the loss of function Chk1. The Msc1 protein appears to be important or histone modifications of chromatin, for genomic stability and for survival after DNA damage. Experiments described in this proposal aim to dissect the role of the Msc1 protein in fission yeast, to lay the groundwork for understanding the functions of the human homologues.

描述（由申请人提供）：细胞周期检查点确保从一个复制细胞周期到下一个复制细胞周期的基因组完整性。如果基因组遭受灾难性损伤，多细胞真核生物的细胞可能会发生凋亡，大概是为了将它们从细胞群中消除，并降低遗传不稳定细胞繁殖的风险。或者，细胞可能通过细胞周期的短暂停滞来对 DNA 损伤做出反应，这与它们在暴露于 DNA 损伤剂时的存活能力相关。这种反应需要 DNA 损伤检查点途径；如果受到突变或药物治疗的影响，细胞将进入有丝分裂，DNA 受损并死亡。裂殖酵母是识别和表征 DNA 损伤检查点成分的极其有价值的系统。事实上，现在已知在哺乳动物细胞检查点通路中发挥作用的许多蛋白质仅根据其与酵母中遗传和功能鉴定的蛋白质的序列同源性来鉴定。因此，很明显，利用经典遗传学的力量鉴定酵母中的蛋白质是鉴定和深入了解哺乳动物对应物功能的有效且富有成效的方法。该提案中描述的实验将继续研究蛋白激酶 Chk1，它是真核细胞检查点的关键调节因子。此外，我们将重点关注一种新型裂殖酵母蛋白 Msc1。 Msc1 与哺乳动物 RbBP2（一种通过结合肿瘤抑制蛋白 Rb 的能力而被鉴定的蛋白质）和 PLU-1（乳腺癌细胞中上调基因的产物）具有同源结构域。克隆Msc1是因为它可以弥补Chk1功能的缺失。 Msc1 蛋白似乎对染色质的组蛋白修饰很重要，对于基因组稳定性和 DNA 损伤后的存活而言。该提案中描述的实验旨在剖析 Msc1 蛋白在裂殖酵母中的作用，为理解人类同源物的功能奠定基础。