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The Role of LEM Domain Proteins in Nuclear Function

LEM 结构域蛋白在核功能中的作用

基本信息

批准号：
10439450
负责人：
PAMELA K. GEYER
金额：
$ 38.53万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10439450
关键词：
ATR checkpoint Adult Affect Binding Binding Proteins CHEK2 gene Cell Death Cell Maintenance Cells Cessation of life Chromatin Chromosomes Clustered Regularly Interspaced Short Palindromic Repeats Complex Cyst Cytology DNA DNA Damage Data Defect Deformity Development Disease Disease model Drosophila genus Failure Family Fatty acid glycerol esters Functional disorder Gene Expression Profile Genes Genetic Genome Germ Cells Health Heterochromatin High-Throughput RNA Sequencing Homeostasis Human Interphase Cell Lead Link Membrane Mitosis Monitor Mutation Nuclear Nuclear Envelope Nuclear Inner Membrane Nuclear Lamina Nuclear Structure Ontology Pathway interactions Phenotype Phosphotransferases Play Premature aging syndrome Proteins Role Shapes Signal Pathway Signal Transduction Skeletal Muscle Skin Stress Structural defect Structure Tertiary Protein Structure Testing Tissues Transcriptional Activation Variant adult stem cell barrier-to-autointegration factor base bone delta protein ds-DNA experimental study germline stem cells histone-binding proteins improved knock-down mutant novel overexpression prevent response sensor stem cell homeostasis stem cell population stem cell survival stem cells therapeutic development tool transcription factor transcriptome

项目摘要

ABSTRACT Human laminopathies are caused by mutations in genes encoding nuclear lamina (NL) proteins. These proteins form an extensive network that lies beneath the inner nuclear membrane. A unifying disease model suggests that lost tissue homeostasis is due to a failure to maintain adult stem cells. Although NL proteins responsible for laminopathies have been identified, it remains unclear how these proteins maintain healthy stem cell populations and promote tissue homeostasis. The conserved NL family of LEM-domain (LEM-D) proteins play a critical role in building nuclear structure and the NL. LEM-D proteins bind Barrier-to-Autointegration Factor (BAF), a conserved double stranded DNA and histone binding protein. Interactions between LEM-D proteins and BAF target nuclear membranes to chromosomes during nuclear assembly after mitosis. In addition, LEM-D proteins interact with BAF to tether the genome to the nuclear periphery and establish repressed chromatin domains in non-dividing cells. We investigate the Drosophila LEM-D family, focusing on Otefin, a LEM-D protein that is required for survival of adult germline stem cells (GSCs). The otefin mutant GSCs carry structural deformities of the NL and chromatin changes that are shared with laminopathic cells. My lab discovered that these mutant GSCs die because of activation of a novel checkpoint pathway that uses two DNA damage response (DDR) kinases, ATR and Checkpoint kinase 2 (Chk2). Although otefin mutant GSCs carry DNA damage, damage accumulation depends upon Chk2, demonstrating that DNA damage results from checkpoint activation. Based on these and other data, we hypothesize that NL deformation is responsible for activation of ATR and Chk2, a prediction supported by emerging evidence that ATR is a global sensor of structural deformities of cellular components. In this proposal, two Aims are proposed. In Aim 1, we will define the mechanism of ATR/Chk2 activation in otefin mutant GSCs. In Aim 2, we define Chk2- dependent pathways involved in GSC death. We expect our studies will have a broad impact. Nuclear shape changes are shared features of laminopathies and premature aging syndromes. We predict that activation of the NL checkpoint might contribute to lost stem cell maintenance in these diseases.

摘要