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Global mapping of CARM1 substrates defines enzyme specificity and substrate recognition

Author

Listed:
  • Evgenia Shishkova

    (University of Wisconsin – Madison)

  • Hao Zeng

    (McArdle Laboratory for Cancer Research, University of Wisconsin – Madison
    Present address: Chemical Biology and Therapeutics, Novartis Institutes for Biomedical Research, Cambridge, Massachuetts 02139, USA)

  • Fabao Liu

    (McArdle Laboratory for Cancer Research, University of Wisconsin – Madison)

  • Nicholas W. Kwiecien

    (The Genome Center of Wisconsin, University of Wisconsin – Madison)

  • Alexander S. Hebert

    (The Genome Center of Wisconsin, University of Wisconsin – Madison)

  • Joshua J. Coon

    (University of Wisconsin – Madison
    University of Wisconsin – Madison)

  • Wei Xu

    (McArdle Laboratory for Cancer Research, University of Wisconsin – Madison)

Abstract

Protein arginine methyltransferases (PRMTs) introduce arginine methylation, a post-translational modification with the increasingly eminent role in normal physiology and disease. PRMT4 or coactivator-associated arginine methyltransferase 1 (CARM1) is a propitious target for cancer therapy; however, few CARM1 substrates are known, and its mechanism of substrate recognition is poorly understood. Here we employed a quantitative mass spectrometry approach to globally profile CARM1 substrates in breast cancer cell lines. We identified >130 CARM1 protein substrates and validated in vitro >90% of sites they encompass. Bioinformatics analyses reveal enrichment of proline-containing motifs, in which both methylation sites and their proximal sequences are frequently targeted by somatic mutations in cancer. Finally, we demonstrate that the N-terminus of CARM1 is involved in substrate recognition and nearly indispensable for substrate methylation. We propose that development of CARM1-specific inhibitors should focus on its N-terminus and predict that other PRMTs may employ similar mechanism for substrate recognition.

Suggested Citation

  • Evgenia Shishkova & Hao Zeng & Fabao Liu & Nicholas W. Kwiecien & Alexander S. Hebert & Joshua J. Coon & Wei Xu, 2017. "Global mapping of CARM1 substrates defines enzyme specificity and substrate recognition," Nature Communications, Nature, vol. 8(1), pages 1-13, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15571
    DOI: 10.1038/ncomms15571
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    Cited by:

    1. Guozhen Gao & Simone Hausmann & Natasha M. Flores & Ana Morales Benitez & Jianjun Shen & Xiaojie Yang & Maria D. Person & Sitaram Gayatri & Donghang Cheng & Yue Lu & Bin Liu & Pawel K. Mazur & Mark T., 2023. "The NFIB/CARM1 partnership is a driver in preclinical models of small cell lung cancer," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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