title: Loss of the N-terminal methyltransferase NRMT1 increases sensitivity to DNA damage and promotes mammary oncogenesis.
abstract: 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.
authors.affiliation: Department of Biochemistry & Molecular Genetics, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY, USA.
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Bonsignore
authors.affiliation: Department of Biochemistry & Molecular Genetics, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY, USA.
authors.forename: Jill Sergesketter
authors.initials: JS
authors.lastname: Butler
authors.affiliation: Department of Biochemistry & Molecular Genetics, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY, USA.
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Klinge
authors.affiliation: Department of Biochemistry & Molecular Genetics, Center for Genetics and Molecular Medicine, University of Louisville School of Medicine, Louisville, KY, USA.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Schaner Tooley
mesh_terms: D045744:Cell Line, Tumor; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair; D006801:Humans; D008745:Methylation; D008780:Methyltransferases / Q000235:genetics* / Q000378:metabolism*; D013379:Substrate Specificity / Q000502:physiology
chemical_list: D008780:Methyltransferases; C551913:NTMT1 protein, human
keywords: DNA damage; DNA repair; N-terminal methylation; NRMT1; breast cancer