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| Item Type: | Article |
|---|---|
| Title: | Genetic alterations of the SUMO isopeptidase SENP6 drive lymphomagenesis and genetic instability in diffuse large B-cell lymphoma |
| Creators Name: | Schick, M., Zhang, L., Maurer, S., Maurer, H.C., Isaakaidis, K., Schneider, L., Patra, U., Schunck, K., Rohleder, E., Hofstetter, J., Baluapuri, A., Scherger, A.K., Slotta-Huspenina, J., Hettler, F., Weber, J., Engleitner, T., Maresch, R., Slawska, J., Lewis, R., Istvanffy, R., Habringer, S., Steiger, K., Baiker, A., Oostendorp, R.A.J., Miething, C., Lenhof, H.P., Bassermann, F., Chapuy, B., Wirth, M., Wolf, E., Rad, R., Müller, S. and Keller, U. |
| 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. |
| Keywords: | Carbon-Nitrogen Lyases, Chromatin, Cysteine Endopeptidases, DNA Damage, DNA Repair, Diffuse Large B-Cell Lymphoma, Genomic Instability, Inbred C57BL Mice, Mutation, Poly(ADP-ribose) Polymerase Inhibitors, Poly(ADP-ribose) Polymerases, Post-Translational Protein Processing, Sumoylation, Synthetic Lethal Mutations, Transgenic Mice, Tumor Biomarkers, Xenograft Model Antitumor Assays, Animals, Mice |
| Source: | Nature Communications |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Volume: | 13 |
| Number: | 1 |
| Page Range: | 281 |
| Date: | 12 January 2022 |
| Official Publication: | https://doi.org/10.1038/s41467-021-27704-8 |
| PubMed: | View item in PubMed |
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