Facilitated recruitment of MYC to chromatin by interaction with WDR5

项目总结 MYC是一种癌蛋白转录因子，在癌症中发挥重要作用。作为一种转录因子， MYC识别其靶基因的能力对其活性至关重要。长期存在的如何 MYC选择的目标是它与MAX二聚化，形成一个结合特定DNA序列的模块 在靶基因的调控元件中。然而，近年来，靶基因已经变得很明显 MYC的识别还依赖于额外的染色质驻留蛋白，这些蛋白通过亲和力作用于 将MYC：最大二聚体定向到基因组中的特定位置。这种“促进招聘”的过程很糟糕 理解，尽管它可能影响癌细胞中大多数MYC与染色质的结合。详细 为了理解MYC的这一最基本的方面，需要对促进招聘的机制进行研究 活动，而且是及时的，因为与MYC不同，这些招聘人员可能会服从药物发现， 在临床上解锁针对MYC的新方法。本项目探索了以下机制和意义 WDR5促进MYC向染色质的募集，WDR5是一种保守的核蛋白，是一个活性靶点 用于众多团体的药物发现。WDR5招募MYC到对蛋白质至关重要的基因染色质 合成，包括一系列核糖体蛋白基因和编码翻译因子和 核仁RNA。在先前存在的恶性肿瘤中干扰MYC与WDR5的相互作用促进快速和 不可逆转的肿瘤塌陷，表明MYC-WDR5网络可以作为一种药物抑制 治疗由MYC引发的癌症。这个项目的目标1使用了高分辨率基因， 基因组和蛋白质组方法来描述导致MYC和MYC WDR5一起在染色质上，并揭示了WDR5-和其他人促进招募的程度 招聘人员-确定癌细胞中由MYC控制的基因。Aim 2混合了遗传， 基因组和体内研究，以探索MYC-WDR5连接在一系列不同的 癌症的背景，并准确地揭示这种联系如何靶向促进肿瘤的消退。这些 研究将为MYC的目标基因选择机制带来一个新的和强大的范例， MYC网络中新的和有针对性的漏洞，并展示了基因选择性招聘人员(如 WDR5可用于治疗抑制MYC。重要的是，这些研究还将奠定生物学基础 为WDR5抑制剂作为抗MYC药物在临床上的应用奠定基础。

PROJECT SUMMARY MYC is an oncoprotein transcription factor that features prominently in cancer. As a transcription factor, the ability of MYC to recognize its target genes is paramount to its activity. The long-standing paradigm for how MYC selects its targets is that it dimerizes with MAX, forming a module that binds specific DNA sequences in the regulatory elements of target genes. In recent years, however, it has become clear that target gene recognition by MYC can also depend on additional chromatin-resident proteins that act through avidity to direct MYC:MAX dimers to specific sites in the genome. This 'facilitated recruitment' process is poorly understood, although it likely influences a majority of MYC binding to chromatin in cancer cells. Detailed mechanistic studies of facilitated recruitment are needed to understand this most basic aspect of MYC activity, and are timely because, unlike MYC, these recruiters may be amenable to drug discovery, unlocking new ways to target MYC in the clinic. This project explores the mechanisms and significance of facilitated recruitment of MYC to chromatin by WDR5, a conserved nuclear protein that is an active target for drug discovery by numerous groups. WDR5 recruits MYC to chromatin at genes vital for protein synthesis, including a collection of ribosomal protein genes and genes encoding translation factors and nucleolar RNAs. Disrupting interaction of MYC with WDR5 in a preexisting malignancy promotes rapid and irreversible tumor collapse, indicating that the MYC–WDR5 nexus can be pharmacologically inhibited as a treatment for MYC-driven cancers. Aim 1 of this project uses a combination of high resolution genetic, genomic, and proteomic approaches to characterize the fundamental mechanisms that bring MYC and WDR5 together on chromatin, and to reveal the extent to which facilitated recruitment by WDR5—and other recruiters—determines the genes that are controlled by MYC in cancer cells. Aim 2 blends genetic, genomic, and in vivo studies to probe the importance of the MYC–WDR5 connection in a diverse set of cancer contexts, and to reveal precisely how targeting this connection promotes tumor regression. These studies will lead to a new and robust paradigm for the mechanisms of target gene selection by MYC, identify novel and targetable vulnerabilities in the MYC network, and show how gene-selective recruiters such as WDR5 can be exploited to therapeutically inhibit MYC. Importantly, these studies will also lay the biological groundwork for the implementation of WDR5 inhibitors in the clinic as anti-MYC agents.