1. Biochemistry and Chemical Biology
  2. Genetics and Genomics
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Genetic analysis reveals functions of atypical polyubiquitin chains

  1. Fernando Meza Gutierrez
  2. Deniz Simsek
  3. Arda Mizrak
  4. Adam Deutschbauer
  5. Hannes Braberg
  6. Jeffrey Johnson
  7. Jiewei Xu
  8. Michael Shales
  9. Michelle Nguyen
  10. Raquel Tamse-Kuehn
  11. Curt Palm
  12. Lars M Steinmetz
  13. Nevan J Krogan
  14. David P Toczyski  Is a corresponding author
  1. University of California, San Francisco, United States
  2. Amgen Research, United States
  3. Lawrence Berkeley National Laboratory, United States
  4. Stanford University, United States
  5. University of California San Francisco, United States
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Cite this article as: eLife 2018;7:e42955 doi: 10.7554/eLife.42955

Abstract

Although polyubiquitin chains linked through all lysines of ubiquitin exist, specific functions are well-established only for lysine-48 and lysine-63 linkages in Saccharomyces cerevisiae. To uncover pathways regulated by distinct linkages, genetic interactions between a gene deletion library and a panel of lysine-to-arginine ubiquitin mutants were systematically identified. The K11R mutant had strong genetic interactions with threonine biosynthetic genes. Consistently, we found that K11R mutants import threonine poorly. The K11R mutant also exhibited a strong genetic interaction with a subunit of the anaphase-promoting complex (APC), suggesting a role in cell cycle regulation. K11-linkages are important for vertebrate APC function, but this was not previously described in yeast. We show that the yeast APC also modifies substrates with K11-linkages in vitro, and that those chains contribute to normal APC-substrate turnover in vivo. This study reveals comprehensive genetic interactomes of polyubiquitin chains and characterizes the role of K11-chains in two biological pathways.

Article and author information

Author details

  1. Fernando Meza Gutierrez

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5601-7202
  2. Deniz Simsek

    Amgen Research, South San Francisco, United States
    Competing interests
    Deniz Simsek, is affiliated with Amgen Research. The author has no other competing interests to declare..
  3. Arda Mizrak

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  4. Adam Deutschbauer

    Lawrence Berkeley National Laboratory, Berkeley, United States
    Competing interests
    No competing interests declared.
  5. Hannes Braberg

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  6. Jeffrey Johnson

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  7. Jiewei Xu

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  8. Michael Shales

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  9. Michelle Nguyen

    Stanford Genome Technology Center, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.
  10. Raquel Tamse-Kuehn

    Stanford Genome Technology Center, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.
  11. Curt Palm

    Stanford Genome Technology Center, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.
  12. Lars M Steinmetz

    Genetics, Stanford University, Stanford, United States
    Competing interests
    No competing interests declared.
  13. Nevan J Krogan

    Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  14. David P Toczyski

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    For correspondence
    dpt4darwin@gmail.com
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5924-0365

Funding

National Institutes of Health (R35 GM118104)

  • David P Toczyski

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Michael Rape, University of California, Berkeley, United States

Publication history

  1. Received: October 18, 2018
  2. Accepted: November 30, 2018
  3. Accepted Manuscript published: December 14, 2018 (version 1)
  4. Version of Record published: December 24, 2018 (version 2)

Copyright

© 2018, Meza Gutierrez et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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