Abstract
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.
Highlights
Post-translational modifications with small ubiquitin-related modifiers (SUMOs) function as decisive regulatory switches in multiple pathways (Flotho and Melchior, 2013)
Proteomic profiling reveals a network of SENP6 functions at the crossroads of chromatin organization and DNA damage response (DDR)
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
Summary
Post-translational modifications with small ubiquitin-related modifiers (SUMOs) function as decisive regulatory switches in multiple pathways (Flotho and Melchior, 2013). SUMO is covalently linked via its C terminus to an ε-acceptor lysine of the target protein. The best characterized binding module, termed SUMO-interacting motif (SIM), is composed of a hydrophobic core that is occasionally flanked by acidic or phosphorylatable serine or threonine residues (Stehmeier and Muller, 2009). The preferred residue for SUMO chain formation is lysine 11, but alternative linkage types on any of the other lysine residues in SUMO2 or SUMO3 are found (Gartner et al, 2018). The biological role of SUMO chain function is not understood in all facets, but it is clear that SUMO chains can prime proteins for subsequent ubiquitylation by SUMO targeted ubiquitin ligases (StUbLs) (Ulrich, 2008; Vertegaal, 2010). The common characteristic of RNF4 and RNF111 is an array of tandemly repeated SIMs mediating their selective binding to multi- or polySUMOylated target proteins. RNF4 catalyzes the formation of both proteolytic K48-linked and non-proteolytic
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