Bonsignore Lindsay A, Butler Jill Sergesketter, Klinge Carolyn M, Schaner Tooley Christine E
Department of Biochemistry & Molecular Genetics, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY, USA.
Oncotarget. 2015 May 20;6(14):12248-63. doi: 10.18632/oncotarget.3653.
Though discovered over four decades ago, the function of N-terminal methylation has mostly remained a mystery. Our discovery of the first mammalian N-terminal methyltransferase, NRMT1, has led to the discovery of many new functions for N-terminal methylation, including regulation of DNA/protein interactions, accurate mitotic division, and nucleotide excision repair (NER). Here we test whether NRMT1 is also important for DNA double-strand break (DSB) repair, and given its previously known roles in cell cycle regulation and the DNA damage response, assay if NRMT1 is acting as a tumor suppressor. We find that NRMT1 knockdown significantly enhances the sensitivity of breast cancer cell lines to both etoposide treatment and γ-irradiation, as well as, increases proliferation rate, invasive potential, anchorage-independent growth, xenograft tumor size, and tamoxifen sensitivity. Interestingly, this positions NRMT1 as a tumor suppressor protein involved in multiple DNA repair pathways, and indicates, similar to BRCA1 and BRCA2, its loss may result in tumors with enhanced sensitivity to diverse DNA damaging chemotherapeutics.
尽管四十年前就已发现N端甲基化，但它的功能大多仍是个谜。我们发现了首个哺乳动物N端甲基转移酶NRMT1，这一发现揭示了N端甲基化的许多新功能，包括对DNA/蛋白质相互作用的调控、精确的有丝分裂以及核苷酸切除修复（NER）。在此，我们测试NRMT1对DNA双链断裂（DSB）修复是否也很重要，并鉴于其在细胞周期调控和DNA损伤反应中的已知作用，分析NRMT1是否起到肿瘤抑制作用。我们发现，敲低NRMT1会显著增强乳腺癌细胞系对依托泊苷处理和γ射线照射的敏感性，同时还会提高增殖率、侵袭能力、非锚定依赖性生长、异种移植肿瘤大小以及对他莫昔芬的敏感性。有趣的是，这表明NRMT1是一种参与多种DNA修复途径的肿瘤抑制蛋白，并且与BRCA1和BRCA2类似，其缺失可能导致肿瘤对多种DNA损伤化疗药物的敏感性增强。
