Mechanisms of translation regulation by N4-acetylcytidine in cancer cells

N4-乙酰胞苷在癌细胞中的翻译调控机制

• 批准号: 10468324
• 负责人: Daniel Arango
• 金额: $ 24.9万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10468324
• 关键词: Ablation; Acetylation; Acetyltransferase; Acute Myelocytic Leukemia; Affect; Antibodies; Anticodon; Base Pairing; Bioinformatics; Biological Process; Cancer Cell Growth; Career Mobility; Cell Proliferation; Cells; Chemicals; Code; Codon Nucleotides; Data; Deposition; Development Plans; Enzymes; Exhibits; Foundations; Gene Expression Regulation; Generations; Genetic Code; Goals; Growth; Health; Hematopoietic; Human; Human Genetics; Intramural Research Program; Knowledge; Leadership; Light; Malignant Neoplasms; Mentors; Messenger RNA; Modification; Molecular; National Cancer Institute; Normal Cell; Nucleotides; Pathway interactions; Phase; Post-Translational Protein Processing; Postdoctoral Fellow; Prevalence; Process; RNA; Regulation; Research; Research Proposals; Resources; Role; Solid; Testing; Therapeutic; Thermodynamics; Training; Transcript; Transfer RNA; Translational Regulation; Translations; Universities; acute myeloid leukemia cell; base; cancer cell; cancer therapy; career; career development; druggable target; epitranscriptome; novel; novel therapeutic intervention; programs; skills

Project Summary/Abstract Translation of messenger RNAs (mRNA) is commonly dysregulated in cancer cells, highlighting regulatory mechanisms in translation as potential targets for cancer treatment. Chemical modifications of mRNA, known as the epitranscriptome, have emerged as a new layer of translation regulation. Yet, the types and prevalence of mRNA modifications as well as their roles in cancer remain poorly understood. N4-acetylcytidine (ac4C) is a novel mRNA modification that directly enhances translation efficiency of target mRNAs, representing a new and significant layer of translational regulation. Of substantial relevance to cancer, the enzyme that catalyzes the deposition of ac4C, N-acetyltransferase 10 (NAT10), is commonly dysregulated in cancers, whereas NAT10 depletion specifically decreases growth of cancer cells, including acute myeloid leukemia (AML) cells. In light of these observations, this proposal stipulates that NAT10-catalyzed ac4C promotes proliferation of AML cells by enhancing translation efficiency. During the K99 phase, this study aims to investigate the molecular mechanisms of mRNA acetylation (Aim 1) and the mechanisms by which ac4C promotes translation efficiency (Aim 2). In the R00 phase, this proposal aims to evaluate whether NAT10-catalyzed ac4C promotes AML growth by enhancing translation of proliferation-promoting factors (Aim 3). The overall long-term goals of this study are to expand our understanding of the epitranscriptome and the mechanisms that dynamically regulate translation efficiency in cancer cells, using this knowledge to implement novel therapeutic strategies for human conditions where translation is altered, including AML and other cancers. My career goal is to develop an independent high-quality research program for the benefit of human health. To achieve these goals, I built a career development plan which includes this research proposal and a plan for training, mentoring and networking to expand my research, bioinformatical, leadership and mentoring skills. The K99 phase will be developed in the Intramural Research Program of the National Cancer Institute (NCI) and will be mentored by Dr. Shalini Oberdoerffer (NCI), and co- mentored by Dr. Jeffery Coller (Case Western Reserve University). The NCI Intramural Research Program offers strong well-established research programs and multiple resources for career development and transition of postdoctoral fellows.

项目概要/摘要 信使 RNA (mRNA) 的翻译在癌细胞中通常失调，突出了监管 转化为癌症治疗潜在靶标的机制。 mRNA 的化学修饰，称为 表观转录组已成为翻译调控的新层。然而，其类型和流行程度 mRNA 修饰及其在癌症中的作用仍然知之甚少。 N4-乙酰胞苷 (ac4C) 是 新颖的 mRNA 修饰可直接提高目标 mRNA 的翻译效率，代表了一种新的、 重要的翻译调控层。与癌症密切相关的是，催化 ac4C、N-乙酰转移酶 10 (NAT10) 的沉积在癌症中通常失调，而 NAT10 耗竭特别会降低癌细胞的生长，包括急性髓系白血病（AML）细胞。鉴于 根据这些观察结果，该提案规定 NAT10 催化的 ac4C 通过以下方式促进 AML 细胞的增殖： 提高翻译效率。在K99阶段，本研究旨在研究分子机制 mRNA 乙酰化（目标 1）以及 ac4C 促进翻译效率的机制（目标 2）。在 R00阶段，该提案旨在评估NAT10催化的ac4C是否通过增强 增殖促进因子的翻译（目标 3）。这项研究的总体长期目标是扩大我们的 了解表观转录组和动态调节翻译效率的机制 癌细胞，利用这些知识来实施针对人类疾病的新治疗策略 翻译发生改变，包括 AML 和其他癌症。我的职业目标是培养独立高素质 造福人类健康的研究计划。为了实现这些目标，我制定了职业发展计划 其中包括本研究提案以及旨在扩展我的研究的培训、指导和网络计划， 生物信息、领导和指导技能。 K99阶段将在校内研究中开发 美国国家癌症研究所 (NCI) 的项目，将由 Shalini Oberdoerffer 博士 (NCI) 和合作者指导 由 Jeffery Coller 博士（凯斯西储大学）指导。 NCI 校内研究计划提供 强大而完善的研究计划和多种资源用于职业发展和转型 博士后研究员。