Expanding the biological roles of N-terminal methylation

扩大 N 末端甲基化的生物学作用

• 批准号: 10330681
• 负责人: Christine E Schaner-Tooley
• 金额: $ 39.57万
• 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/10330681
• 关键词: Aging; Bacteria; Binding Proteins; Biochemistry; Biological; Breast Cancer Cell; Cell Compartmentation; Cell Survival; Code; Consensus Sequence; DNA-Protein Interaction; Disease; Enzymes; Goals; Growth; Histones; Human; Knock-out; Kyphosis deformity of spine; Malignant Neoplasms; Mammals; Methylation; Methyltransferase; Mus; Myosin Light Chains; N-terminal; Pattern; Phenotype; Physiological; Play; Post-Translational Protein Processing; Premature aging syndrome; Process; Proteins; Regulation; Role; Therapeutic; age related; amino group; cell growth; loss of function; migration; skin fibrosis; stem cell fate; tumorigenesis

Project Summary: Post-translational modification of N-terminal α-amino groups is a highly conserved and vastly utilized process seen in all species from bacteria to mammals. Dr. Schaner Tooley pioneered the field of N-terminal methylation by identifying the first two eukaryotic N-terminal methyltransferases, NRMT1 and NRMT2. She went on to characterize the consensus sequence of these enzymes, identify dozens of their substrates, and show N-terminal 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, kyphosis, and dermal fibrosis. They now want to expand understanding of the biochemistry of NRMT1 regulation, identify additional substrates regulated by the Nα-PTM code, and mechanistically characterize a newly discovered role for NRMT1 in stem cell fate determination. Successful completion of these goals will provide a more global understanding of NRMT1 function and help better develop NRMT1 as a therapeutic for human cancers and age-related disorders.

项目总结： N-末端α-氨基的翻译后修饰是一个高度保守和被广泛利用的过程 在从细菌到哺乳动物的所有物种中都能看到。Schaner Toey博士开创了N-末端领域 通过鉴定前两个真核N-末端甲基转移酶NRMT1和NRMT2进行甲基化。她 接着描述了这些酶的共同序列，鉴定了它们的数十种底物，并 显示N-末端甲基化调节蛋白质/DNA的相互作用。她的实验室也是第一个证明这一点的，就像 组蛋白PTM，Nα-PTM是功能编码的一部分。他们发现了第一种已知存在于这两种食物中的蛋白质 N-α-乙酰和N-α-甲基形式，肌球蛋白轻链9(MYL9)。他们证明了这两个N个α-PTM 创造不同的MYL9蛋白形式，具有独特的蛋白结合伙伴、内部PTM模式和细胞 隔间特定的功能。他们还证明了NRMT1在肿瘤发生中的重要作用 和衰老。乳腺癌细胞中NRMT1的缺失促进了增殖、迁移、克隆形成和 包裹体生长。小鼠的NRMT1基因敲除促进了与早衰相关的表型， 包括早期白发、脊柱后凸和皮肤纤维化。他们现在想要扩大对 NRMT1调控的生物化学，鉴定由Nα-Ptm编码调控的额外底物，以及 对新发现的NRMT1在干细胞命运决定中的作用进行机械表征。成功 这些目标的完成将提供对NRMT1功能的更全面的了解，并有助于更好地 开发NRMT1作为治疗人类癌症和年龄相关疾病的药物。