Loss of SENP6 drives genetic instability in B-cell lymphoma

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 identified 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 is associated with DNA repair deficiency. To test, if the SENP6 status is critical for genome maintenance in vivo, we performed low coverage WGS of primary murine B-cell lymphomas with and without CRISPR/Cas9 mediated Senp6 deletion