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.

项目概要： N-末端α-氨基（Nα）的翻译后修饰是一种高度保守和广泛应用的蛋白质修饰。 从细菌到哺乳动物的所有物种都有这个过程。Schaner Tooley博士开创了Nα- 通过鉴定前两种真核Nα-甲基转移酶，NRMT 1和NRMT 2（也称为NRMT 2）， 胃L11 A和胃L11 B）。她继续描述这些酶的共有序列， 鉴定了几十种底物，并显示Nα-甲基化调节蛋白质/DNA相互作用。她的实验室 也是第一个表明，像组蛋白PTM，Nα-PTM是一个功能代码的一部分。他们发现了第一个 已知蛋白质以Nα-乙酰基和Nα-甲基形式存在，即肌球蛋白轻链9（MYL 9）。他们 证明这两个Nα-PTM产生了MYL 9的不同蛋白形式，具有独特的蛋白结合 合作伙伴，内部PTM模式，和细胞室特异性功能。他们还证明了 NRMT 1在肿瘤发生和衰老中的重要作用。乳腺癌细胞中NRMT 1的缺失促进 增殖、迁移、集落形成和异种移植生长。NRMT 1敲除小鼠促进 与过早衰老相关的表型，包括早期白发和脱发、脊柱后凸、皮肤和肝脏 纤维化、神经变性、记忆丧失和寿命缩短。他们已经证明NRMT 1调节 神经和肌肉干细胞发育，并假设NRMT 1在干细胞发育中的一般作用。 分化驱动许多过早老化表型。他们现在想要1.）扩大理解 NRMT 1调节的生物化学，2.）鉴别Nα-PTM代码规定的其他底物， 和3.）在干细胞命运决定中NRMT 1的新发现的作用的机制特征。 本多样性补充文件中提出的工作将解决第一点，并审查对 NRMT 1通过结合其胃L家族同系物NRMT 2和胃L13。虽然越来越明显 甲基转移酶调节的常用方法是通过与相近同系物形成复合物， NRMT 1是已知的第一个由两种不同同源物反向调节的甲基转移酶。这里我们 将研究这些相互作用的生物化学和生物学相关性。成功完成这些 实验不仅将进一步发展NRMT 1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的训练，在技术和 继续从事药物设计研究所需的专业技能。