权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Defining WASp-dependent pathways in replication stress

定义复制应激中的 WASp 依赖性途径

基本信息

批准号：
10708353
负责人：
YATIN M VYAS
金额：
$ 56.29万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-07 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10708353
关键词：
ANGPTL2 gene Actins Adaptor Signaling Protein Address Autoimmunity Biological Cell Lineage Cell Nucleus Cell Survival Cell membrane Cell physiology Cells Child Classification Clinical Compensation Cytoplasm Cytoskeleton Cytosol DNA DNA Damage DNA Repair DNA biosynthesis DNA replication fork Databases Defect Deposition Diagnosis Disease Disease Progression Drosophila genus Etiology Family member Fanconi Anemia pathway Fanconi&apos s Anemia Functional disorder G Actin Genes Genetic Transcription Genome Genome Stability Genomic Instability Genotype Golgi Apparatus Human Hybrids Immune Immune System Diseases Immunodeficiency and Cancer Impairment Infection Knowledge Laboratories Link Lymphocyte Malignant - descriptor Malignant Neoplasms Measures Mediating Missense Mutation Molecular Mus Mutagens Mutation Non-Malignant Nonsense Mutation Normal Cell Nuclear Organism Paper Pathogenicity Pathway interactions Patients Phenotype Plants Play Polymers Predisposition Process Protein Deficiency Protein Family Proteins RNA Receptor Signaling Reporting Research Role SS DNA BP Shapes Signal Transduction Single-Stranded DNA Site Stress Testing Time Tumor Suppressor Proteins Wiskott-Aldrich Syndrome X Chromosome Xenopus Yeasts autoinflammation autoreactivity biological adaptation to stress cancer predisposition chromatin remodeling cofactor congenital immunodeficiency homologous recombination human disease hydroxyurea monomer mortality mutant novel patient subsets polymerization prevent protein function repair function repaired replication factor A replication stress response tumorigenesis

项目摘要

Perturbation in the replication-stress response (RSR) and DNA damage response (DDR) causes genomic-instability. Replication protein A (RPA) is a single-strand DNA (ssDNA) binding protein with key roles in the RSR and DDR. Genomic-instability occurs in Wiskott-Aldrich syndrome (WAS), a primary immunodeficiency and cancer susceptibility disorder, yet the molecular underpinnings of unstable genome in WAS cells remain uncharacterized. WASp, the protein deficient in this disorder, functions both in the cytoplasm and nucleus. In the nucleus, WASp functions to prevent the accumulation of harmful R loops (RNA-DNA hybrids + ssDNA) and in the pre-repair step of escorting broken DNA ends to the repair sites by the homology-directed repair (HDR) pathway. Accordingly, WAS patient lymphocytes are poorly-equipped to both prevent and resolve DNA damage, which proposes WAS as a “genotoxin-sensitive” immune dysregulation disorder. Our foundational studies have uncovered an essential role of WASp in the RSR by influencing RPA functions under hydroxyurea-induced replication stress, in both immune and nonimmune cells. Therefore, the overall objective of this proposal is to explicate the molecular details of how WASp safeguards normal replication and which proteins and pathways WASp associates with to enable this function during replicative stress. We will test the hypothesis that WASp is required to both prevent and manage replication stress and DNA damage. Specifically, we will define WASp role in mechanisms that process a blocked replication fork (in Aim 1) and address how WASp role specifically on modifying the actin state (G-actin vs. F-actin) influence RSR (in Aim 2). Achieving these aims will propose WASp as a novel RSR factor, and human WAS as a disease of dysfunctional RSR, which may provide new mechanisms for oncogenesis in WAS.

复制-应激反应（RSR）和DNA损伤反应（DDR）引起的扰动