Arginine methylation controls growth regulation by E2F-1

Er Chieh Cho, Shunsheng Zheng, Shonagh Munro, Geng Liu, Simon M. Carr, Jutta Moehlenbrink, Yi Chien Lu, Lindsay Stimson, Omar Khan, Rebecca Konietzny, Joanna McGouran, Amanda S. Coutts, Benedikt Kessler, David J. Kerr, Nicholas B La Thangue

Research output: Contribution to journalArticle

108 Citations (Scopus)

Abstract

E2F transcription factors are implicated in diverse cellular functions. The founding member, E2F-1, is endowed with contradictory activities, being able to promote cell-cycle progression and induce apoptosis. However, the mechanisms that underlie the opposing outcomes of E2F-1 activation remain largely unknown. We show here that E2F-1 is directly methylated by PRMT5 (protein arginine methyltransferase 5), and that arginine methylation is responsible for regulating its biochemical and functional properties, which impacts on E2F-1-dependent growth control. Thus, depleting PRMT5 causes increased E2F-1 protein levels, which coincides with decreased growth rate and associated apoptosis. Arginine methylation influences E2F-1 protein stability, and the enhanced transcription of a variety of downstream target genes reflects increased E2F-1 DNA-binding activity. Importantly, E2F-1 is methylated in tumour cells, and a reduced level of methylation is evident under DNA damage conditions that allow E2F-1 stabilization and give rise to apoptosis. Significantly, in a subgroup of colorectal cancer, high levels of PRMT5 frequently coincide with low levels of E2F-1 and reflect a poor clinical outcome. Our results establish that arginine methylation regulates the biological activity of E2F-1 activity, and raise the possibility that arginine methylation contributes to tumourigenesis by influencing the E2F pathway.

Original languageEnglish
Pages (from-to)1785-1797
Number of pages13
JournalEMBO Journal
Volume31
Issue number7
DOIs
Publication statusPublished - Apr 4 2012
Externally publishedYes

Keywords

  • Arginine methylation
  • cancer
  • E2F-1
  • growth control

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)

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  • Cite this

    Cho, E. C., Zheng, S., Munro, S., Liu, G., Carr, S. M., Moehlenbrink, J., Lu, Y. C., Stimson, L., Khan, O., Konietzny, R., McGouran, J., Coutts, A. S., Kessler, B., Kerr, D. J., & Thangue, N. B. L. (2012). Arginine methylation controls growth regulation by E2F-1. EMBO Journal, 31(7), 1785-1797. https://doi.org/10.1038/emboj.2012.17