Regulation of NRMT1 through homolog binding

通过同源物结合调节 NRMT1

• 批准号: 10571563
• 负责人: Christine E Schaner-Tooley
• 金额: $ 3.84万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10571563
• 关键词: Address; Aging; Bacteria; Binding; Binding Proteins; Biochemical; Biochemistry; Biological; Breast Cancer Cell; Cell Compartmentation; Cell Survival; Code; Complex; Consensus Sequence; DNA-Protein Interaction; Development; Disease; Drug Design; Enzymes; Family; Family member; Growth; Hair; Histones; Homologous Gene; Human; Knock-out; Kyphosis deformity of spine; Liver Fibrosis; Longevity; Malignant Neoplasms; Mammals; Memory Loss; Methods; Methylation; Methyltransferase; Mus; Muscle satellite cell; Myosin Light Chains; N-terminal; Nerve Degeneration; Pattern; Phenotype; Physiological; Play; Post-Translational Protein Processing; Premature aging syndrome; Process; Proteins; Regulation; Research; Role; Stem Cell Development; Therapeutic; Training; Work; age related; amino group; career; cell growth; experimental study; loss of function; migration; relating to nervous system; skills; skin fibrosis; stem cell differentiation; stem cell fate; therapeutic target; tumorigenesis

Project Summary: Post-translational modification of N-terminal α-amino (Nα) groups is a highly conserved and vastly utilized process seen in all species from bacteria to mammals. Dr. Schaner Tooley pioneered the field of Nα- methylation by identifying the first two eukaryotic Nα-methyltransferases, NRMT1 and NRMT2 (also known as METTL11A and METTL11B). She went on to characterize the consensus sequence of these enzymes, identify dozens of their substrates, and show Nα-methylation regulates protein/DNA interactions. Her lab was also the first to show that, like histone PTMs, Nα-PTMs are part of a functional code. They identified the first protein known to exist in both Nα-acetyl and Nα-methyl forms, Myosin Light Chain 9 (MYL9). They demonstrated that these two Nα-PTMs create distinct proteoforms of MYL9, with unique protein binding partners, internal PTM patterns, and cell compartment-specific functions. They have also demonstrated important roles for NRMT1 in oncogenesis and aging. NRMT1 loss in breast cancer cells promotes proliferation, migration, colony formation, and xenograph growth. NRMT1 knockout in mice promotes phenotypes associated with premature aging, including, early graying and hair loss, kyphosis, skin and liver fibrosis, neurodegeneration, memory loss, and decreased lifespan. They have shown that NRMT1 regulates both neural and muscle stem cell development, and hypothesize a general role for NRMT1 in stem cell differentiation drives many of the premature aging phenotypes. They now want to 1.) expand understanding of the biochemistry of NRMT1 regulation, 2.) identify additional substrates regulated by the Nα-PTM code, and 3.) mechanistically characterize the newly discovered role for NRMT1 in stem cell fate determination. The worked proposed in this diversity supplement will address the first point and examine the regulation of NRMT1 through binding of its METTL family homologs, NRMT2 and METTL13. While it is becoming apparent that a common method of methyltransferase regulation is through complex formation with close homologs, NRMT1 is the first methyltransferase known to be opposingly regulated by two different homologs. Here we will study both the biochemistry and biological relevance of these interactions. Successful completion of these experiments will not only further the development of NRMT1 as a potential therapeutic target for human cancers and age-related disorders, but also complete Haley Parker's training in the technical and professional skills necessary to continue a research career in drug design.

项目摘要： N末端α-氨基（Nα）组的翻译后修饰是一种高度保守的，并且已广泛使用 从细菌到哺乳动物的所有物种中都看到的过程。 Schaner Tooley博士开创了Nα-领域 通过鉴定前两个真核Nα-甲基转移酶NRMT1和NRMT2（也称为称为 mettl11a和mettl11b）。她继续描述了这些酶的共识序列， 识别数十个底物，并显示Nα-甲基化调节蛋白质/DNA相互作用。她的实验室是 同样，第一个表明像组蛋白PTM一样，Nα-PTMS是功能代码的一部分。他们确定了第一个 已知蛋白质存在于Nα-乙酰基和Nα-甲基形式，肌球蛋白轻链9（MYL9）中。他们 证明这两个Nα-PTM会产生MYL9的独特蛋白质成型，具有独特的蛋白质结合 合作伙伴，内部PTM模式和细胞室特异性功能。他们也证明了 NRMT1在肿瘤发生和衰老中的重要作用。乳腺癌细胞中的NRMT1损失促进 增殖，迁移，菌落形成和Xenographing生长。小鼠的NRMT1淘汰赛促进 与过早衰老相关的表型，包括早期灰色和脱发，脑膜病，皮肤和肝脏 纤维化，神经退行性，记忆丧失和改善的寿命。他们已经表明NRMT1调节 神经和肌肉干细胞的发育，并假设NRMT1在干细胞中的一般作用 分化驱动了许多早熟表型。他们现在想1。）扩展理解 NRMT1法规的生物化学2。）确定由Nα-PTM代码调节的其他底物， 3.）机械地表征了NRMT1在干细胞脂肪测定中的新发现的作用。 这种多样性补充剂提出的工作将解决第一点，并检查监管 NRMT1通过其METTL家族同源物NRMT2和METTL13的结合。虽然变得显而易见 一种常见的甲基转移酶调节方法是通过与紧密同源物的复杂形成， NRMT1是第一个已知受两个不同同源物对相反调节的甲基转移酶。我们在这里 将研究这些相互作用的生物化学和生物学相关性。这些成功完成 实验不仅将进一步发展NRMT1作为人类的潜在治疗靶点 癌症和与年龄有关的疾病，但也完成了海莉·帕克（Haley Parker）的技术和 继续从事药物设计研究工作所需的专业技能。