A novel enzymatic activity of WSTF and its role in tumorigenesis

我的长期研究兴趣是研究表观遗传机制来抑制肿瘤发生。最近 研究表明，异常增殖诱导的DNA损伤反应（DDR）可能是导致细胞凋亡的重要因素之一， 在肿瘤发生的早期阶段的屏障，以防止基因组的不稳定性。复员方案早期阶段的一个标志 组蛋白H2A.X S139磷酸化（H2A.X）。这种磷酸化作用是 以其在DNA诱导的DDR期间形成的紧密染色质结构的分界而闻名 破坏剂。与这些观察结果一致，H2A.X缺乏加速了肿瘤的进展。 小鼠中p53缺陷背景。我们的初步研究已经确定了一个新的标记磷酸化， H2A.X，酪氨酸142及其激酶，WSTF（William-Beuren综合征转录因子），基因 在人类William-Beuren综合征（WS）中经常缺失。我们的研究表明，WSTF 通过其非常规激酶结构域具有内在酪氨酸激酶活性， 任何已知的激酶折叠。有趣的是，我们最近的数据表明，WSTF和ATM可能会形成一个 调节DNA损伤处理诱导的DDR的“前馈”环，包括H2A.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， 可以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是否 功能由ATM/R激酶调节。此阶段的一个并行目标是开发H2 A. X“设计器 与Tom Muir博士的实验室（洛克菲勒大学）合作。在独立阶段，我将 测试WSTF在基因修饰小鼠模型中抑制肿瘤发生的功能。的目标 指导阶段（一年）是为独立阶段开发关键方法和试剂， 超越。同时，我将申请独立的职位。Drs. Allis的优越环境 缪尔的实验室将促进我在指导阶段的研究，以及我向独立研究的过渡。 调查员独立阶段（3年）的拟议研究将为启动我的 未来的研究，以确定新的表观遗传机制，以抑制肿瘤发生。

My long term research Interest is to investigate epigenetic mechanisms to suppress tumorigenesis. Recent studies suggest that the DNA 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 H2A.X). This phosphorylation event is well-known for its demarcation of compact chromatin structures formed during DDR induced by DNA 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 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.