Impact of pathogenic missense mutations on the ARID domain of ARID1a

致病性错义突变对 ARID1a ARID 结构域的影响

基本信息

批准号：
10654137
负责人：
Hugo Sanabria
金额：
$ 44.31万
依托单位：
CLEMSON UNIVERSITY
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：
2023-04-12 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10654137
关键词：
ARID Domain ARID1A gene Affinity Amino Acids Binding Bioinformatics Biomedical Research Biophysics Breast Cancer Patient Cell Proliferation Cholangiocarcinoma Chromatin Chromatin Remodeling Factor Classification Clinical Trials Complex Computer Models DNA DNA Binding DNA Binding Domain DNA Repair DNA biosynthesis DNA-Protein Interaction Databases Environment Fluorescence Fluorescence Resonance Energy Transfer Fostering Foundations Frameshift Mutation Future Gene Expression Genes Genetic Transcription Goals Health Health Benefit Helix-Turn-Helix Motifs Libraries Malignant Neoplasms Malignant neoplasm of ovary Measures Missense Mutation Modeling Molecular Mechanisms of Action Mutate Mutation Names Non-Small-Cell Lung Carcinoma Nuclear Outcome Ovarian Pancreas Pathogenicity Pathway interactions Patients Physical condensation Positioning Attribute Prevention Program Development Property Protein Family Proteins Research Research Training Science Solid Neoplasm Spectrum Analysis Structural Models Structure Structure-Activity Relationship Sucrose System Talents Testing The Cancer Genome Atlas Therapeutic Tumor Suppressor Genes Tumor Suppressor Proteins Universities Uterus Work alpha helix anticancer research biobank biophysical analysis career career development design experience experimental study fighting graduate student improved insight interest loss of function loss of function mutation member mutant novel therapeutics personalized medicine physical science programs protein folding resistance mutation screening single molecule temporal measurement translational oncology undergraduate student

项目摘要

SUMMARY The AT-rich interacting domain-containing protein 1a (ARID1a), also named BAF250a, p270, or hOSA1, is a vital component of the Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex. ARID1a, as part of the SWI/SNF complex, is responsible for crucial nuclear activities, including regulating transcription, DNA synthesis, DNA damage repair, and cell proliferation. Consequently, ARID1a is classified as a tumor suppressor gene and it is frequently mutated in solid tumor malignancies cancers, amounting to ~6% of every cancer and ~45% of all ovarian cancers. Loss of function mutations in ARID1a due to frameshift, stop-gain, or missense mutations leads to dysregulation of many gene pathways, including the prevention of tumor suppressor activities. Although the loss of function is evident in stop-gain and frameshift mutations, the impact of pathogenic missense mutations is subtler and more difficult to understand or predict. We hypothesize that pathogenic missense mutations impact the protein stability, DNA binding affinity, and structural dynamics, perturbing its function. Specifically, we seek to understand the effects of pathogenic missense mutations in the ARID domain of ARID1a, which is responsible for its direct interaction with DNA. Therefore, the broad goal of this research program is to understand the effects of pathogenic missense mutations in the ARID domain of ARID1a. The long-term implications of this program are the development of a unique framework that will pave the way for directly probing identified pathogenic missense mutations for future guided patient-specific screening therapeutic approaches. Our proposed study integrates biophysical studies, computational approaches, and single-molecule spectroscopy to characterize the stability, DNA binding, and structural dynamics of the ARID domain. Our studies will give insights into the correlation between missense pathogenic mutations and the structure-dynamics- function relationship. The PI and our research team are uniquely positioned to pursue the following specific aims: (1) to determine the impact of pathogenic missense mutations on the stability of the ARID domain; (2) to determine the impact of pathogenic missense mutations in the binding affinity of ARID domain to DNA; and (3) to determine the changes in the structure and dynamics of ARID domain as perturbed by pathogenic missense mutations. This interdisciplinary project will engage undergraduates in research to foster their interest and career development in both physical sciences and cancer research. The expected outcome will be a structural model of ARID1a’s ARID domain interaction with DNA, a library of pathogenic mutations ranked by the impact on stability and affinity, a system to improve pathogenic predictors, and the foundation for developing novel therapeutics and personalized medicine in the fight against cancer.

概括富含相互作用域的含蛋白1A（ARID1A），也称为BAF250A，P270或HOSA1，是重要的开关/蔗糖不可发酵（SWI/SNF）染色质重塑复合物的组成部分。 Arid1a，作为一部分 SWI/SNF复合物的负责核活动，包括调节转录，DNA 合成，DNA损伤修复和细胞增殖。因此，ARID1A被归类为肿瘤抑制剂基因，并且经常在实体瘤恶性肿瘤中突变，占每种癌症的6％，所有卵巢癌的45％。由于移架，定格或错过而导致的ARID1A功能突变损失突变导致许多基因途径的失调，包括预防肿瘤抑制活性。尽管功能的丧失是暂停和移码突变的证据，但致病错过的影响突变是微妙的，更难理解或预测。我们假设那个致病错过突变会影响蛋白质稳定性，DNA结合亲和力和结构动力学，从而扰乱其功能。具体而言，我们试图了解病原体错义突变在ARID1A的干旱结构域中的影响，这是导致其与DNA直接相互作用的原因。因此，该研究计划的广泛目标是了解致病性错义突变在ARID1A的干旱结构域中的影响。长期该程序的含义是一个独特的框架的开发，该框架将为直接探测铺平道路为未来的患者特异性筛查方法确定了致病性错义突变。我们提出的研究整合了生物物理研究，计算方法和单分子谱图表征干旱结构域的稳定性，DNA结合和结构动力学。我们的研究将深入了解错义致病突变与结构动力学之间的相关性 - 功能关系。 PI和我们的研究团队的独特位置可以追求以下特定目标：（1）确定致病错义突变对干旱结构域稳定性的影响；（2）至确定致病性错义突变在干旱结构域与DNA的结合亲和力中的影响；（3）确定因致病错过而扰动干旱域的结构和动力学的变化突变。这个跨学科项目将吸引本科生，以促进他们的兴趣和职业物理科学和癌症研究的发展。预期的结果将是一个结构模型 ARID1A与DNA的干旱结构域相互作用，DNA的病原突变库，由对影响的影响稳定性和亲和力，一种改善致病预测因子的系统，以及开发新颖的基础在抗癌斗争中的治疗和个性化医学。