Browse
Submit Data
Databases
API
Help

Dataset Information

18 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

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.

SUBMITTER: Schick M

PROVIDER: S-EPMC8755833 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

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

Project description: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 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 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.

2021-07-16 | GSE180052 | GEO

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

Project description:Actionable genetic alterations of the SUMO isopeptidase SENP6 drive lymphomagenesis and genetic instability in diffuse large B-cell lymphoma

| PRJNA746335 | ENA

Targetable genetic alterations of TCF4 (E2-2) drive immunoglobulin expression in diffuse large B cell lymphoma.

Project description:The activated B cell (ABC-like) subtype of diffuse large B cell lymphoma (DLBCL) is characterized by chronic activation of signaling initiated by immunoglobulin ? (IgM). By analyzing the DNA copy number profiles of 1000 DLBCL tumors, we identified gains of 18q21.2 as the most frequent genetic alteration in ABC-like DLBCL. Using integrative analysis of matched gene expression profiling data, we found that the TCF4 (E2-2) transcription factor gene was the target of these alterations. Overexpression of TCF4 in ABC-like DLBCL cell lines led to its occupancy on immunoglobulin (IGHM) and MYC gene enhancers and increased expression of these genes at the transcript and protein levels. Inhibition of TCF4 activity with dominant-negative constructs was synthetically lethal to ABC-like DLBCL cell lines harboring TCF4 DNA copy gains, highlighting these gains as an attractive potential therapeutic target. Furthermore, the TCF4 gene was one of the top BRD4-regulated genes in DLBCL cell lines. BET proteolysis-targeting chimera (PROTAC) ARV771 extinguished TCF4, MYC, and IgM expression and killed ABC-like DLBCL cells in vitro. In DLBCL xenograft models, ARV771 treatment reduced tumor growth and prolonged survival. This work highlights a genetic mechanism for promoting immunoglobulin signaling in ABC-like DLBCL and provides a functional rationale for the use of BET inhibitors in this disease.

| S-EPMC6724184 | biostudies-literature

DeSUMOylating isopeptidase: a second class of SUMO protease.

Project description:The modification of proteins by small ubiquitin-like modifier (SUMO) is crucial for the regulation of diverse cellular processes. Protein SUMOylation is reversed by isopeptidases, collectively known as deSUMOylases. Only one family of SUMO-specific proteases has been described so far: the sentrin-specific proteases (SENP). Here, we identify and characterize a new deSUMOylase, which we have named DeSI-1 (DeSumoylating Isopeptidase 1). We describe BZEL—a new transcriptional repressor—as substrate of DeSI-1. DeSI-1 catalyses the deSUMOylation, but not the deubiquitination, of BZEL. Furthermore, the SENP substrates PML and ΔNp63 are not deSUMOylated by DeSI-1, suggesting that SENP and DeSI enzymes recognize different sets of substrates. Together, these data identify a second class of SUMO proteases.

| S-EPMC3321169 | biostudies-literature

Swapping small ubiquitin-like modifier (SUMO) isoform specificity of SUMO proteases SENP6 and SENP7.

Project description:SUMO proteases can regulate the amounts of SUMO-conjugated proteins in the cell by cleaving off the isopeptidic bond between SUMO and the target protein. Of the six members that constitute the human SENP/ULP protease family, SENP6 and SENP7 are the most divergent members in their conserved catalytic domain. The SENP6 and SENP7 subclass displays a clear proteolytic cleavage preference for SUMO2/3 isoforms. To investigate the structural determinants for such isoform specificity, we have identified a unique sequence insertion in the SENP6 and SENP7 subclass that is essential for their proteolytic activity and that forms a more extensive interface with SUMO during the proteolytic reaction. Furthermore, we have identified a region in the SUMO surface determinant for the SUMO2/3 isoform specificity of SENP6 and SENP7. Double point amino acid mutagenesis on the SUMO surface allows us to swap the specificity of SENP6 and SENP7 between the two SUMO isoforms. Structure-based comparisons combined with biochemical and mutagenesis analysis have revealed Loop 1 insertion in SENP6 and SENP7 as a platform to discriminate between SUMO1 and SUMO2/3 isoforms in this subclass of the SUMO protease family.

| S-EPMC3195590 | biostudies-literature

Negative regulation of TLR inflammatory signaling by the SUMO-deconjugating enzyme SENP6.

Project description:The signaling of Toll-like receptors (TLRs) induces host defense against microbial invasion. Protein posttranslational modifications dynamically shape the strength and duration of the signaling pathways. It is intriguing to explore whether de-SUMOylation could modulate the TLR signaling. Here we identified SUMO-specific protease 6 (SENP6) as an intrinsic attenuator of the TLR-triggered inflammation. Depletion of SENP6 significantly potentiated the NF-?B-mediated induction of the proinflammatory genes. Consistently, SENP6-knockdown mice were more susceptible to endotoxin-induced sepsis. Mechanistically, the small ubiquitin-like modifier 2/3 (SUMO-2/3) is conjugated onto the Lysine residue 277 of NF-?B essential modifier (NEMO/IKK?), and this impairs the deubiquitinase CYLD to bind NEMO, thus strengthening the inhibitor of ?B kinase (IKK) activation. SENP6 reverses this process by catalyzing the de-SUMOylation of NEMO. Our study highlights the essential function of the SENP family in dampening TLR signaling and inflammation.

| S-EPMC3694847 | biostudies-literature

The SUMO protease SENP6 is a direct regulator of PML nuclear bodies.

Project description:Promyelocytic leukemia protein (PML) is the core component of PML-nuclear bodies (PML NBs). The small ubiquitin-like modifier (SUMO) system (and, in particular, SUMOylation of PML) is a critical component in the formation and regulation of PML NBs. SUMO protease SENP6 has been shown previously to be specific for SUMO-2/3-modified substrates and shows preference for SUMO polymers. Here, we further investigate the substrate specificity of SENP6 and show that it is also capable of cleaving mixed chains of SUMO-1 and SUMO-2/3. Depletion of SENP6 results in accumulation of endogenous SUMO-2/3 and SUMO-1 conjugates, and immunofluorescence analysis shows accumulation of SUMO and PML in an increased number of PML NBs. Although SENP6 depletion drastically increases the size of PML NBs, the organizational structure of the body is not affected. Mutation of the catalytic cysteine of SENP6 results in its accumulation in PML NBs, and biochemical analysis indicates that SUMO-modified PML is a substrate of SENP6.

| S-EPMC3016979 | biostudies-literature

Recruitment of a SUMO isopeptidase to rDNA stabilizes silencing complexes by opposing SUMO targeted ubiquitin ligase activity.

Project description:Post-translational modification by SUMO (small ubiquitin-like modifier) plays important but still poorly understood regulatory roles in eukaryotic cells, including as a signal for ubiquitination by SUMO targeted ubiquitin ligases (STUbLs). Here, we delineate the molecular mechanisms for SUMO-dependent control of ribosomal DNA (rDNA) silencing through the opposing actions of a STUbL (Slx5:Slx8) and a SUMO isopeptidase (Ulp2). We identify a conserved region in the Ulp2 C terminus that mediates its specificity for rDNA-associated proteins and show that this region binds directly to the rDNA-associated protein Csm1. Two crystal structures show that Csm1 interacts with Ulp2 and one of its substrates, the rDNA silencing protein Tof2, through adjacent conserved interfaces in its C-terminal domain. Disrupting Csm1's interaction with either Ulp2 or Tof2 dramatically reduces rDNA silencing and causes a marked drop in Tof2 abundance, suggesting that Ulp2 promotes rDNA silencing by opposing STUbL-mediated degradation of silencing proteins. Tof2 abundance is rescued by deletion of the STUbL SLX5 or disruption of its SUMO-interacting motifs, confirming that Tof2 is targeted for degradation in a SUMO- and STUbL-dependent manner. Overall, our results demonstrate how the opposing actions of a localized SUMO isopeptidase and a STUbL regulate rDNA silencing by controlling the abundance of a key rDNA silencing protein, Tof2.

| S-EPMC5435892 | biostudies-literature

TMEM30A loss-of-function mutations drive lymphomagenesis and confer therapeutically exploitable vulnerability in B-cell lymphoma.

Project description:Transmembrane protein 30A (TMEM30A) maintains the asymmetric distribution of phosphatidylserine, an integral component of the cell membrane and 'eat-me' signal recognized by macrophages. Integrative genomic and transcriptomic analysis of diffuse large B-cell lymphoma (DLBCL) from the British Columbia population-based registry uncovered recurrent biallelic TMEM30A loss-of-function mutations, which were associated with a favorable outcome and uniquely observed in DLBCL. Using TMEM30A-knockout systems, increased accumulation of chemotherapy drugs was observed in TMEM30A-knockout cell lines and TMEM30A-mutated primary cells, explaining the improved treatment outcome. Furthermore, we found increased tumor-associated macrophages and an enhanced effect of anti-CD47 blockade limiting tumor growth in TMEM30A-knockout models. By contrast, we show that TMEM30A loss-of-function increases B-cell signaling following antigen stimulation-a mechanism conferring selective advantage during B-cell lymphoma development. Our data highlight a multifaceted role for TMEM30A in B-cell lymphomagenesis, and characterize intrinsic and extrinsic vulnerabilities of cancer cells that can be therapeutically exploited.

| S-EPMC8480332 | biostudies-literature

Targetable genetic alterations of TCF4 (E2-2) drive immunoglobulin expression in the activated B-cell subtype of diffuse large B-cell lymphoma.

Project description:This SuperSeries is composed of the SubSeries listed below.

2019-04-18 | GSE119477 | GEO