Journal
CELL REPORTS
Volume 29, Issue 2, Pages 480-+Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2019.08.106
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Funding
- European Union/BMBF Horizon 2020 consortium SUBLYMe
- Deutsche Krebshilfe grant [111944]
- Wilhelm Sander Stiftung
- Stiftung Charite
- DFG collaborative research centers [SFB815, 1177, 1335]
- LOEWE UbNet
- DFG [MU-1764/4]
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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 response (DDR). SENP6 acts as a SUMO eraser at 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. SENP6 deficiency impairs chromatin association of the ATR cofactor ATRIP, thereby compromising the activation of Chk1 signaling in response to aphidicolin-induced replicative stress and sensitizing cells to DNA damage. We propose a general role of SENP6 in orchestrating chromatin dynamics and genome stability networks by balancing chromatin residency of protein complexes.
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