Expanding the biological roles of N-terminal methylation

项目概要： N-末端α-氨基的翻译后修饰是一个高度保守和广泛应用的过程 从细菌到哺乳动物的所有物种都有。Schaner Tooley博士开创了N-末端 通过鉴定前两种真核生物N-末端甲基转移酶NRMT 1和NRMT 2来鉴定甲基化。她 接着描述了这些酶的共有序列，鉴定了几十种底物， 显示N-末端甲基化调节蛋白质/DNA相互作用。她的实验室也是第一个证明， 组蛋白PTM，Nα-PTM是功能代码的一部分。他们发现了第一种已知存在于两种细胞中的蛋白质， Nα-乙酰基和Nα-甲基形式，肌球蛋白轻链9（MYL 9）。他们证明了这两种Nα-PTM 创建MYL 9的不同蛋白形式，具有独特的蛋白结合伴侣，内部PTM模式和细胞 特定功能区。他们还证明了NRMT 1在肿瘤发生中的重要作用 和衰老。乳腺癌细胞中NRMT 1的缺失促进增殖、迁移、集落形成和细胞周期的改变。 异种移植生长。NRMT 1敲除小鼠促进与过早衰老相关的表型， 包括早期变灰、脊柱后凸和皮肤纤维化。他们现在想扩大对 NRMT 1调控的生物化学，鉴定由Nα-PTM编码调控的其他底物，以及 在干细胞命运决定中NRMT 1的新发现的作用的机制特征。成功 这些目标的完成将提供对NRMT 1功能的更全面的理解，并有助于更好地 开发NRMT 1作为人类癌症和年龄相关疾病的治疗药物。

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.