Wnt5a Signals through DVL1 to Repress Ribosomal DNA Transcription by RNA Polymerase I

Randall A. Dass, Aishe A. Sarshad, Brittany B. Carson, Jennifer M. Feenstra, Amanpreet Kaur, Ales Obrdlik, Matthew M. Parks, Varsha Prakash, Damon K. Love, Kristian Pietras, Rosa Serra, Scott C. Blanchard, Piergiorgio Percipalle, Anthony M.C. Brown, C. Theresa Vincent

Research output: Contribution to journalArticle

Abstract

Ribosome biogenesis is essential for cell growth and proliferation and is commonly elevated in cancer. Accordingly, numerous oncogene and tumor suppressor signaling pathways target rRNA synthesis. In breast cancer, non-canonical Wnt signaling by Wnt5a has been reported to antagonize tumor growth. Here, we show that Wnt5a rapidly represses rDNA gene transcription in breast cancer cells and generates a chromatin state with reduced transcription of rDNA by RNA polymerase I (Pol I). These effects were specifically dependent on Dishevelled1 (DVL1), which accumulates in nucleolar organizer regions (NORs) and binds to rDNA regions of the chromosome. Upon DVL1 binding, the Pol I transcription activator and deacetylase Sirtuin 7 (SIRT7) releases from rDNA loci, concomitant with disassembly of Pol I transcription machinery at the rDNA promoter. These findings reveal that Wnt5a signals through DVL1 to suppress rRNA transcription. This provides a novel mechanism for how Wnt5a exerts tumor suppressive effects and why disruption of Wnt5a signaling enhances mammary tumor growth in vivo.

Original languageEnglish (US)
Article numbere1006217
JournalPLoS genetics
Volume12
Issue number8
DOIs
StatePublished - Aug 2016

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

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  • Cite this

    Dass, R. A., Sarshad, A. A., Carson, B. B., Feenstra, J. M., Kaur, A., Obrdlik, A., Parks, M. M., Prakash, V., Love, D. K., Pietras, K., Serra, R., Blanchard, S. C., Percipalle, P., Brown, A. M. C., & Vincent, C. T. (2016). Wnt5a Signals through DVL1 to Repress Ribosomal DNA Transcription by RNA Polymerase I. PLoS genetics, 12(8), [e1006217]. https://doi.org/10.1371/journal.pgen.1006217