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

Markus Schick, Le Zhang, Sabine Maurer, Hans Carlo Maurer, Konstandina Isaakaidis, Lara Schneider, Upayan Patra, Kathrin Schunck, Elena Rohleder, Julia Hofstetter, Apoorva Baluapuri, Anna Katharina Scherger, Julia Slotta-Huspenina, Franziska Hettler, Julia Weber, Thomas Engleitner, Roman Maresch, Jolanta Slawska, Richard Lewis, Rouzanna Istvanffy, Stefan Habringer, Katja Steiger, Armin Baiker, Robert A. J. Oostendorp, Cornelius Miething, Hans-Peter Lenhof, Florian Bassermann, Björn Chapuy, Matthias Wirth, Elmar Wolf, Roland Rad, Stefan Müller () and Ulrich Keller ()
Additional contact information
Markus Schick: corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
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
Thomas Engleitner: Technische Universität München
Roman Maresch: 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
Matthias Wirth: corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin
Elmar Wolf: University of Würzburg
Roland Rad: Technische Universität München
Stefan Müller: Goethe University, Medical School
Ulrich Keller: corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-021-27704-8

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