Dataset Information

Identification of SENP6 target proteins by endogenous SUMO2/3 IP-MS

ABSTRACT: Cellular signaling by the ubiquitin-related SUMO pathway relies on coordinated conjugation and deconjugation events. SUMO-specific deconjugating enzymes counterbalance SUMOylation, but comprehensive insight into their substrate specificity and regulation is missing. By characterizing SENP6 we define an N-terminal multi-SIM domain as critical determinant in targeting SENP6 activity to SUMO chains. Using an integrated proteomic profiling approach we reveal a network of SENP6 functions at the crossroad of chromatin organization and DNA damage response (DDR). SENP6 acts as SUMO eraser on key organizers of telomeric and centromeric chromatin domains and determines the SUMOylation status and chromatin association of the cohesin complex. Importantly, SENP6 is part of the hPSO4/PRP19 complex that drives ATR-Chk1 activation during DDR. Intriguingly, SENP6 deficiency impairs chromatin-association of the ATR cofactor ATRIP thereby compromising the activation of Chk1 signaling in response to replicative stress and sensitizing cells to replicative stress-induced DNA damage. Collectively, we propose a general role of SENP6 in orchestrating chromatin dynamics and genome stability networks by balancing chromatin-residency of protein complexes.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Hela Cell

DISEASE(S): Cervix Carcinoma

SUBMITTER: Kathrin Schunck

LAB HEAD: Prof. Dr. Stefan Müller

PROVIDER: PXD015134 | Pride | 2019-11-20

REPOSITORIES: Pride

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Publications

The SUMO Isopeptidase SENP6 Functions as a Rheostat of Chromatin Residency in Genome Maintenance and Chromosome Dynamics.

Wagner Kristina K Kunz Kathrin K Piller Tanja T Tascher Georg G Hölper Soraya S Stehmeier Per P Keiten-Schmitz Jan J Schick Markus M Keller Ulrich U Müller Stefan S

Cell reports 20191001 2

Signaling by the ubiquitin-related SUMO pathway relies on coordinated conjugation and deconjugation events. SUMO-specific deconjugating enzymes counterbalance SUMOylation, but comprehensive insight into their substrate specificity and regulation is missing. By characterizing SENP6, we define an N-terminal multi-SIM domain as a critical determinant in targeting SENP6 to SUMO chains. Proteomic profiling reveals a network of SENP6 functions at the crossroads of chromatin organization and DNA damage ...[more]

PMID: 31597105

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Project description:Activation of the MLL-ENL-ERtm oncogene initiates aberrant proliferation of myeloid progenitors. Here, we show induction of a fail-safe mechanism mediated by the DNA damage response (DDR) machinery that results in activation of the ATR/ATM-Chk1/Chk2-p53/p21 checkpoint and cellular senescence at early stages of cellular transformation caused by a regulatable MLL-ENL-ERtm in mice. Furthermore, we identified the transcription program underlying this intrinsic anti-cancer barrier, and DDR-induced inflammatory regulators that fine-tune the signaling towards senescence, thereby modulating the fate of MLL-ENL-immortalized cells in a tissue-environment-dependent manner. Our results indicate that DDR is a rate-limiting event for acquisition of stem cell-like properties in MLL-ENL-ERtm-mediated transformation, as experimental inhibition of the barrier accelerated the transition to immature cell states and acute leukemia development. We created a mouse model wherein the protein function of the MLL-ENL oncogene depends on tamoxifen due to fusion with the mutated estrogen-binding domain of the estrogen receptor (ERtm). After 7 months of tamoxifen administration, the MLL-ENL-ERtm mice developed a myeloproliferative disease, which progressed into the terminal stage after a long period (mean survival: 592 ± 112 days) of continuous tamoxifen provision. We have profiled gene expression at three time-points of tamoxifen treatment corresponding to three distinct cellular states of the MLL-ENL-ERtm-induced myeloproliferation in the bone marrow: 1. 7 months - high proliferation state with low DDR signaling (4 biological replicates), 2. 7-8 months - the transition period of lower proliferation and high DDR activity (4 biogical replicates) and 3. 8 months - the senescence (3 biological replicates). Time-matched tamoxifen-treated wild-type bone marrow analysed in 4 biological replicates. We have profiled gene expression in three disease stages in the spleen: 1. 7 months - early stage - induced proliferation and DDR (3 biological replicates), 2. 9-10 months - progression - partial senescence and DDR is maintained (3 biological replicates) and 3. 16-23 months - terminal stage - proliferation, low or absent DDR and no senescence (3 biological replicates). Time-matched tamoxifen-treated and age-matched wild-type spleens analysed in 5 biological replicates.

Dataset Information

Identification of SENP6 target proteins by endogenous SUMO2/3 IP-MS

Publications

The SUMO Isopeptidase SENP6 Functions as a Rheostat of Chromatin Residency in Genome Maintenance and Chromosome Dynamics.

Similar Datasets

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