Facilitated recruitment of MYC to chromatin by interaction with WDR5

通过与 WDR5 相互作用促进 MYC 募集至染色质

• 批准号: 10440489
• 负责人: William Patrick Tansey
• 金额: $ 39.36万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10440489
• 关键词: Attention; Automobile Driving; Avidity; Behavior; Binding; Binding Proteins; Biological; CRISPR screen; Cell Survival; Cells; Cessation of life; Characteristics; Chromatin; Clinic; Clinical; Collection; DNA; DNA Binding; DNA Sequence; Data; Development; Drug Targeting; Exposure to; Family; Foundations; Gene Expression; Gene Proteins; Genes; Genetic; Genetic Transcription; Genome; Genomics; Goals; Grant; Heart; Human; MYC Family Protein; MYC gene; Maintenance; Malignant Neoplasms; Metabolism; Modeling; Molecular; Nuclear; Nuclear Protein; Oncogenic; Oncoproteins; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Process; Protein Biosynthesis; Proteins; Proteomics; Proto-Oncogene Proteins c-myc; RNA; Regulatory Element; Resolution; Ribosomal Proteins; Role; Site; Therapeutic; Time; United States; Work; base; cancer cell; cancer therapy; cell growth; dimer; drug discovery; genome integrity; genome-wide; in vivo; inhibitor; innovation; malignant state; mouse model; neoplastic cell; novel; novel therapeutics; overexpression; recruit; response; stem; transcription factor; transcriptomics; translation factor; tumor; tumorigenesis; tumorigenic

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.

项目摘要 MYC是一种癌蛋白转录因子，在癌症中具有显著特征。作为转录因子， MYC识别其靶基因的能力对其活性至关重要。长期以来， MYC选择它的目标是它与MAX二聚化，形成结合特定DNA序列的模块 在靶基因的调控元件中。然而，近年来，人们已经清楚地认识到，靶基因 MYC的识别还依赖于其他染色质驻留蛋白，这些蛋白通过亲合力作用于 将MYC：MAX二聚体定向至基因组中的特定位点。这种“便利的招聘”过程很糟糕 尽管它可能影响大多数MYC与癌细胞中染色质的结合。详细 为了理解MYC的这个最基本的方面，需要对促进性招募进行机制研究 活动，并且是及时的，因为与MYC不同，这些招募者可能适合药物发现， 开启了在临床上瞄准MYC的新方法。本项目探讨了 通过WDR 5促进MYC向染色质的募集，WDR 5是一种保守的核蛋白， 被许多团体用于药物发现。WDR 5将MYC招募到对蛋白质至关重要的基因的染色质中 合成，包括核糖体蛋白基因和编码翻译因子的基因的集合， 核仁RNA在预先存在的恶性肿瘤中破坏MYC与WDR 5的相互作用促进了快速和有效的生长。 不可逆的肿瘤崩溃，表明MYC-WDR 5关系可以被抑制， 治疗MYC驱动的癌症。该项目的目标1使用高分辨率遗传学， 基因组学和蛋白质组学方法来表征MYC的基本机制， 为了揭示WDR 5-和其他基因在多大程度上促进了WDR 5-和其他基因的募集， 招募者-决定癌细胞中由MYC控制的基因。目标2融合了基因， 基因组和体内研究，以探测MYC-WDR 5连接在一组不同的 癌症背景，并精确揭示如何靶向这种联系促进肿瘤消退。这些 这些研究将为MYC选择靶基因的机制提供一个新的、强大的范例， MYC网络中的新的和有针对性的漏洞，并显示基因选择性招聘人员，如 WDR 5可以用于治疗性抑制MYC。重要的是，这些研究也将奠定生物学基础。 为在临床上使用WDR 5抑制剂作为抗MYC药物奠定了基础。