A Conserved Splicing Silencer Dynamically Regulates O-GlcNAc Transferase Intron Retention and O-GlcNAc Homeostasis

Sung Kyun Park, Xiaorong Zhou, Kathryn E. Pendleton, Olga V. Hunter, Jennifer J Kohler, Kathryn A O'Donnell-Mendell, Nicholas K Conrad

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Modification of nucleocytoplasmic proteins with O-GlcNAc regulates a wide variety of cellular processes and has been linked to human diseases. The enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) add and remove O-GlcNAc, but the mechanisms regulating their expression remain unclear. Here, we demonstrate that retention of the fourth intron of OGT is regulated in response to O-GlcNAc levels. We further define a conserved intronic splicing silencer (ISS) that is necessary for OGT intron retention. Deletion of the ISS in colon cancer cells leads to increases in OGT, but O-GlcNAc homeostasis is maintained by concomitant increases in OGA protein. However, the ISS-deleted cells are hypersensitive to OGA inhibition in culture and in soft agar. Moreover, growth of xenograft tumors from ISS-deleted cells is compromised in mice treated with an OGA inhibitor. Thus, ISS-mediated regulation of OGT intron retention is a key component in OGT expression and maintaining O-GlcNAc homeostasis.

Original languageEnglish (US)
Pages (from-to)1088-1099
Number of pages12
JournalCell Reports
Volume20
Issue number5
DOIs
StatePublished - Aug 1 2017

Keywords

  • intron retention
  • O-GlcNAc
  • O-GlcNAc homeostasis
  • O-GlcNAc transferase
  • OGA
  • OGT
  • OSMI-1
  • RNA splicing
  • splicing silencer
  • thiamet-G

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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