| Summary: | Summary: 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. : SUMO isopeptidases of the SENP family counterbalance cellular SUMOylation, but their substrate specificity is largely unknown. Using in-depth proteomic profiling, Wagner et al. reveal a network of SENP6 functions at the crossroads of chromatin organization and DNA damage response and define a role of SENP6 in balancing chromatin residency of proteins. Keywords: SUMO, StUbL, SENP6, SUMO chains, cohesion, DNA damage checkpoint, ATR, Chk1, hPSO4, PRP19
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