The SUMO Isopeptidase SENP6 Functions as a Rheostat of Chromatin Residency in Genome Maintenance and Chromosome Dynamics
Kristina Wagner,
Kathrin Kunz,
Tanja Piller,
Georg Tascher,
Soraya Hölper,
Per Stehmeier,
Jan Keiten-Schmitz,
Markus Schick,
Ulrich Keller,
Stefan Müller
Affiliations
Kristina Wagner
Institute of Biochemistry II, Faculty of Medicine, Goethe University, Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany
Kathrin Kunz
Institute of Biochemistry II, Faculty of Medicine, Goethe University, Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany
Tanja Piller
Institute of Biochemistry II, Faculty of Medicine, Goethe University, Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany
Georg Tascher
Institute of Biochemistry II, Faculty of Medicine, Goethe University, Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany
Soraya Hölper
Institute of Biochemistry II, Faculty of Medicine, Goethe University, Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany
Per Stehmeier
Institute of Biochemistry II, Faculty of Medicine, Goethe University, Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany
Jan Keiten-Schmitz
Institute of Biochemistry II, Faculty of Medicine, Goethe University, Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany
Markus Schick
Internal Medicine III, School of Medicine, Technische Universität München, Ismaninger Strasse 22, 81675 Munich, Germany; Department of Hematology, Oncology and Tumor Immunology (Campus Benjamin Franklin), Charité Universitätsmedizin Berlin, Hindenburgdamm 30, 12203 Berlin, Germany
Ulrich Keller
Internal Medicine III, School of Medicine, Technische Universität München, Ismaninger Strasse 22, 81675 Munich, Germany; Department of Hematology, Oncology and Tumor Immunology (Campus Benjamin Franklin), Charité Universitätsmedizin Berlin, Hindenburgdamm 30, 12203 Berlin, Germany; German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
Stefan Müller
Institute of Biochemistry II, Faculty of Medicine, Goethe University, Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany; Corresponding author
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