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Genetic alterations of the SUMO isopeptidase SENP6 drive lymphomagenesis and genetic instability in diffuse large B-cell lymphoma

Author

Listed:
  • Markus Schick

    (corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
    Technische Universität München)

  • Le Zhang

    (corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin)

  • Sabine Maurer

    (Technische Universität München)

  • Hans Carlo Maurer

    (Technische Universität München)

  • Konstandina Isaakaidis

    (corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin)

  • Lara Schneider

    (Saarland University)

  • Upayan Patra

    (Goethe University, Medical School)

  • Kathrin Schunck

    (Goethe University, Medical School)

  • Elena Rohleder

    (corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin)

  • Julia Hofstetter

    (University of Würzburg)

  • Apoorva Baluapuri

    (University of Würzburg)

  • Anna Katharina Scherger

    (Technische Universität München)

  • Julia Slotta-Huspenina

    (Technische Universität München)

  • Franziska Hettler

    (Technische Universität München)

  • Julia Weber

    (Technische Universität München
    Technische Universität München)

  • Thomas Engleitner

    (Technische Universität München
    Technische Universität München)

  • Roman Maresch

    (Technische Universität München
    Technische Universität München)

  • Jolanta Slawska

    (Technische Universität München)

  • Richard Lewis

    (Technische Universität München)

  • Rouzanna Istvanffy

    (Technische Universität München)

  • Stefan Habringer

    (corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin)

  • Katja Steiger

    (Technische Universität München)

  • Armin Baiker

    (Bavarian Health and Food Safety Authority)

  • Robert A. J. Oostendorp

    (Technische Universität München)

  • Cornelius Miething

    (University Medical Center Freiburg)

  • Hans-Peter Lenhof

    (Saarland University)

  • Florian Bassermann

    (Technische Universität München)

  • Björn Chapuy

    (corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
    University Medical Center Göttingen)

  • Matthias Wirth

    (corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin)

  • Elmar Wolf

    (University of Würzburg)

  • Roland Rad

    (Technische Universität München
    Technische Universität München
    German Cancer Research Center (DKFZ))

  • Stefan Müller

    (Goethe University, Medical School)

  • Ulrich Keller

    (corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
    German Cancer Research Center (DKFZ)
    Max-Delbrück-Center for Molecular Medicine)

Abstract

SUMOylation is a post-translational modification of proteins that regulates these proteins’ localization, turnover or function. Aberrant SUMOylation is frequently found in cancers but its origin remains elusive. Using a genome-wide transposon mutagenesis screen in a MYC-driven B-cell lymphoma model, we here identify the SUMO isopeptidase (or deconjugase) SENP6 as a tumor suppressor that links unrestricted SUMOylation to tumor development and progression. Notably, SENP6 is recurrently deleted in human lymphomas and SENP6 deficiency results in unrestricted SUMOylation. Mechanistically, SENP6 loss triggers release of DNA repair- and genome maintenance-associated protein complexes from chromatin thereby impairing DNA repair in response to DNA damages and ultimately promoting genomic instability. In line with this hypothesis, SENP6 deficiency drives synthetic lethality to Poly-ADP-Ribose-Polymerase (PARP) inhibition. Together, our results link SENP6 loss to defective genome maintenance and reveal the potential therapeutic application of PARP inhibitors in B-cell lymphoma.

Suggested Citation

  • Markus Schick & Le Zhang & Sabine Maurer & Hans Carlo Maurer & Konstandina Isaakaidis & Lara Schneider & Upayan Patra & Kathrin Schunck & Elena Rohleder & Julia Hofstetter & Apoorva Baluapuri & Anna K, 2022. "Genetic alterations of the SUMO isopeptidase SENP6 drive lymphomagenesis and genetic instability in diffuse large B-cell lymphoma," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-021-27704-8
    DOI: 10.1038/s41467-021-27704-8
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    References listed on IDEAS

    as
    1. Julia Weber & Jorge Rosa & Carolyn S. Grove & Markus Schick & Lena Rad & Olga Baranov & Alexander Strong & Anja Pfaus & Mathias J. Friedrich & Thomas Engleitner & Robert Lersch & Rupert Öllinger & Mic, 2019. "PiggyBac transposon tools for recessive screening identify B-cell lymphoma drivers in mice," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
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    Cited by:

    1. Laura A. Claessens & Matty Verlaan-de Vries & Ilona J. Graaf & Alfred C. O. Vertegaal, 2023. "SENP6 regulates localization and nuclear condensation of DNA damage response proteins by group deSUMOylation," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Yejinpeng Wang & Lingao Ju & Gang Wang & Kaiyu Qian & Wan Jin & Mingxing Li & Jingtian Yu & Yiliang Shi & Yongzhi Wang & Yi Zhang & Yu Xiao & Xinghuan Wang, 2023. "DNA polymerase POLD1 promotes proliferation and metastasis of bladder cancer by stabilizing MYC," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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