A novel enzymatic activity of WSTF and its role in tumorigenesis

描述（由申请人提供）：我的长期研究兴趣是研究抑制肿瘤发生的表观遗传机制。最近的研究表明，由异常增殖引起的DMA损伤反应（DDR）可能是肿瘤发生早期阻止基因组不稳定的屏障之一。DDR在肿瘤发生早期的一个标志是组蛋白H2A。X S139磷酸化（称为y-H2A.X）。这种磷酸化事件因其在dma损伤剂诱导的DDR过程中形成的致密染色质结构的划分而闻名。根据这些观察，H2A。X缺乏加速了p53缺乏背景下小鼠的肿瘤进展。我们的初步研究已经在H2A上发现了一个新的磷酸化标记。X，酪氨酸142及其激酶，WSTF （William-Beuren综合征转录因子），一个在人类威廉-伯伦综合征（WS）中经常缺失的基因。我们的研究表明，WSTF通过其非常规的激酶结构域具有内在的酪氨酸激酶活性，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可能形成一个“前馈”回路来调节DNA损伤处理（包括y-H2A）诱导的DDR。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。这一阶段的一个平行目标是开发H2A。X”设计师;与汤姆·缪尔博士的实验室（洛克菲勒大学）合作。在独立阶段，我将在转基因小鼠模型中测试WSTF抑制肿瘤发生的功能。指导阶段（1年）的目标是为独立阶段及以后的阶段开发关键的方法和试剂。同时，我将申请独立的职位。dr .。Allis和Muir的实验室将会帮助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）提出的研究将为我未来的研究铺平道路，以确定抑制肿瘤发生的新的表观遗传机制。

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.