A novel enzymatic activity of WSTF and its role in tumorigenesis

我的长期研究兴趣是研究抑制肿瘤发生的表观遗传学机制。近期 研究表明，由异常增殖引起的DNA损伤反应(DDR)可能是 肿瘤发生早期的屏障，以防止基因组不稳定。解甲返乡早期的一个标志 肿瘤发生的机制是组蛋白H_2A.X S139的磷酸化(称为H_2A.X)。这种磷酸化事件是 众所周知，它对DNA诱导的DDR过程中形成的致密染色质结构进行了划分 损害剂。与这些观察相一致的是，H_2A.X缺乏会加速肿瘤的进展。 小鼠的P53基因缺失背景。我们的初步研究已经确定了一个新的标志--磷酸化 酪氨酸142及其激酶，WSTF(William-Beuren综合征转录因子)，一个基因 在人类William-Beuren综合征(WS)中经常缺失。我们的研究表明，WSTF 具有内在的酪氨酸激酶活性，通过其非传统的激活域，没有同源性 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 包括H_2A.X在内的DNA损伤处理诱导DDR的“前馈”环(S139) 磷酸化。WSTF还可能在异常扩散引发的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的发生。在指导阶段，我将测试WSTF 其功能受ATM/R激酶的调节。这一阶段的一个平行目标是开发H2 A.X“Designer 染色质“，与Tom Muir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抑制肿瘤形成的作用。的目标是 指导阶段(第一年)是为独立阶段和 更远一点。同时，我会申请独立的职位。《艾利斯博士》中的绝佳环境 缪尔的实验室将促进我在指导阶段的研究，并帮助我过渡到独立的 调查员。在独立阶段(3年)拟议的研究将为启动我的 未来的研究，以确定新的表观遗传学机制，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.