A novel enzymatic activity of WSTF and its role in tumorigenesis

WSTF 的新酶活性及其在肿瘤发生中的作用

• 批准号: 8036443
• 负责人: zhuo Andrew Xiao
• 金额: $ 7.2万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8036443
• 关键词: Alleles; Biochemical Genetics; Biological Process; C-terminal; Chromatin; Chromatin Remodeling Factor; Chromatin Structure; Complex; DNA Damage; DNA biosynthesis; Data; Defect; Epigenetic Process; Event; Fibrinogen; Generations; Genetic; Genetic Crosses; Genomic Instability; Genomics; Goals; Growth; Heterochromatin; Histone H2A; Histones; Homologous Gene; In Vitro; Knockout Mice; Lead; Link; Maintenance; Malignant Neoplasms; Mammalian Cell; Mediating; Mentors; Molecular; Mus; Mutation; Nucleosomes; Pathway interactions; Patients; Phase; Phosphorylation; Phosphotransferases; Protein Tyrosine Kinase; Proteins; Proteomics; Regulation; Research; Role; Series; Staging; Structure; Substrate Specificity; System; TP53 gene; Testing; Time; Transcription factor genes; Up-Regulation; Variant; Williams Syndrome; Yeasts; base; career; chromatin remodeling; genome-wide; human H2AX protein; human disease; in vivo; mouse model; neoplastic cell; novel; novel therapeutic intervention; prevent; research study; response; transcription factor; tumor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): My long term research interest is to investigate epigenetic mechanisms to suppress tumorigenesis. Recent studies suggest that the DMA damage response (DDR) induced by aberrant proliferation, may be one of the barriers at early stage of tumorigenesis to prevent genomic instability. One hallmark of DDR at early stage of tumorigenesis is histone H2A.X S139 phosphorylation (known as y-H2A.X). This phosphorylation event is well-known for its demarcation of compact chromatin structures formed during DDR induced byDMA damage agents. In keep with these observations, H2A.X deficiency accelerates the tumor progression on a p53 deficient background in mice. Our preliminary studies have identified a new mark phosphorylation on H2A.X, tyrosine 142 and its kinase, WSTF (William-Beuren Syndrome Transcription Factor), a gene frequently deleted in human William-Beuren Syndrome (WS). Our studies have demonstrated that WSTF has an intrinsic tyrosine kinase activity via its unconventional kinase domain, which shares no homology with any known kinase fold. Interestingly, our recent data indicate that the WSTF and ATM may form a "feed- forward" loop to regulate DDR induced by DNA damage treatment, including y-H2A.X (S139) phosphorylation. WSTF may also play a critical role in DDR initiated by aberrant proliferation; therefore, it may suppress tumorigenesis by preventing genomic instability. In the mentored phase, I will test if WSTF function is regulated by the ATM/R kinases. A parallel objective in this phase is to develop H2A.X "designer; chromatin" in collaboration with Dr. Tom Muir's lab (Rockefeller University). In the independent phase, I will test WSTF function for suppressing tumorigenesis in genetically modified mouse models. The goal of the mentored phase (I year) is to develop key methodologies and reagents for the independent phase and beyond. At the same time, I will apply for independent positions. The excellent environment in Drs. Allis and Muir's lab will facilitate my research in the mentored phase and my transition to an independent investigator. The proposed research at the independent phase (3 years) will pave the road to launch my future investigations to identify novel epigenetic mechanisms to suppress tumorigenesis. RELEVANCE: Investigation of WSTF function in preventing genomic instability and tumorigenesis will reveal new mechanisms in human cancer. In addition, these studies will shed light on the molecular mechanisms leading to human William Syndrome, an intractable neurodevelopmental disease.

描述（由申请人提供）：我的长期研究兴趣是研究表观遗传机制，以抑制肿瘤发生。最近的研究表明，异常增殖诱导的DNA损伤反应（DDR）可能是肿瘤发生早期防止基因组不稳定的屏障之一。在肿瘤发生的早期阶段，DDR的一个标志是组蛋白H2 A. X S139磷酸化（称为γ-H2 A.X）。这种磷酸化事件是众所周知的，它的分界紧凑的染色质结构形成的DDR诱导的DMA损伤剂。与这些观察结果一致，H2A.X缺陷加速了小鼠中p53缺陷背景下的肿瘤进展。我们的初步研究发现了一个新的磷酸化标记H2A.X，酪氨酸142及其激酶，WSTF（William-Beuren综合征转录因子），一个在人类William-Beuren综合征（WS）中经常缺失的基因。我们的研究表明，WSTF通过其非常规激酶结构域具有内在的酪氨酸激酶活性，该结构域与任何已知的激酶折叠没有同源性。有趣的是，我们最近的数据表明WSTF和ATM可以形成“前馈”环来调节由DNA损伤处理诱导的DDR，包括γ-H2 A.X（S139）磷酸化。WSTF也可能在异常增殖引发的DDR中发挥关键作用;因此，它可能通过防止基因组不稳定性来抑制肿瘤发生。在指导阶段，我将测试WSTF功能是否受ATM/R激酶的调节。这个阶段的一个平行目标是与Tom Muir博士的实验室（洛克菲勒大学）合作开发H2A.X“设计者;染色质”。在独立的阶段，我将测试WSTF功能抑制肿瘤发生的转基因小鼠模型。指导阶段（一年）的目标是为独立阶段及以后开发关键方法和试剂。同时，我将申请独立的职位。Allis博士和Muir博士实验室的良好环境将有助于我在指导阶段的研究，以及我向独立研究者的过渡。在独立阶段（3年）的拟议研究将为我未来的研究铺平道路，以确定新的表观遗传机制来抑制肿瘤发生。 相关性：研究WSTF在预防基因组不稳定性和肿瘤发生中的功能将揭示人类癌症的新机制。此外，这些研究将揭示导致人类威廉综合征（一种难治性神经发育疾病）的分子机制。