Loss of the N-terminal methyltransferase NRMT1 increases sensitivity to DNA damage and promotes mammary oncogenesis.

Academic Article

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

    Published In

  • Oncotarget  Journal
  • Keywords

  • DNA damage, DNA repair, N-terminal methylation, NRMT1, breast cancer, Cell Line, Tumor, DNA Damage, DNA Repair, Humans, Methylation, Methyltransferases, Substrate Specificity
  • Digital Object Identifier (doi)

    Author List

  • Bonsignore LA; Butler JS; Klinge CM; Schaner Tooley CE
  • Start Page

  • 12248
  • End Page

  • 12263
  • Volume

  • 6
  • Issue

  • 14