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.

项目概要： N 端 α-氨基的翻译后修饰是一个高度保守且广泛利用的过程 Schaner Tooley 博士是 N 末端领域的先驱。 通过识别前两种真核 N 末端甲基转移酶 NRMT1 和 NRMT2 来进行甲基化。 继续表征这些酶的共有序列，识别出数十种底物，并且 她的实验室也是第一个证明 N 末端甲基化调节蛋白质/DNA 相互作用的实验室。 组蛋白 PTM、Nα-PTM 是功能代码的一部分，他们鉴定出了第一个已知存在于两者中的蛋白质。 Nα-乙酰基和 Nα-甲基形式，肌球蛋白轻链 9 (MYL9) 他们证明了这两种 Nα-PTM。 创建 MYL9 的独特蛋白质形式，具有独特的蛋白质结合伴侣、内部 PTM 模式和细胞 它们还证明了 NRMT1 在肿瘤发生中的重要作用。 乳腺癌细胞中 NRMT1 的缺失会促进增殖、迁移、集落形成和衰老。 NRMT1 敲除小鼠的异种生长促进与过早衰老相关的表型， 包括早白、脊柱后凸和皮肤纤维化，他们现在希望扩大对这些疾病的了解。 NRMT1 调节的生物化学，识别受 Nα-PTM 代码调节的其他底物，以及 成功地描述了新发现的 NRMT1 在干细胞命运决定中的作用。 完成这些目标将提供对 NRMT1 功能的更全面的了解，并有助于更好地 开发 NRMT1 作为人类癌症和年龄相关疾病的治疗方法。