Genetic Alterations of the SUMO Isopeptidase SENP6 Drive Lymphomagenesis and Genetic Instability in Diffuse Large B-cell Lymphoma

Overview

Journal Nat Commun

Specialty Biology

Date 2022 Jan 13

PMID 35022408

Authors

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

Bjorn Chapuy

Matthias Wirth

Elmar Wolf

Roland Rad

Stefan Muller

Ulrich Keller

Affiliations

Soon will be listed here.

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.

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