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Summary: Protein aggregates and cytoplasmic vacuolization are major hallmarks of multisystem proteinopathies (MSPs) that lead to muscle weakness. Here, we identify METTL21C as a skeletal muscle-specific lysine methyltransferase. Insertion of a β-galactosidase cassette into the Mettl21c mouse locus revealed that METTL21C is specifically expressed in MYH7-positive skeletal muscle fibers. Ablation of the Mettl21c gene reduced endurance capacity and led to age-dependent accumulation of autophagic vacuoles in skeletal muscle. Denervation-induced muscle atrophy highlighted further impairments of autophagy-related proteins, including LC3, p62, and cathepsins, in Mettl21c−/− muscles. In addition, we demonstrate that METTL21C interacts with the ATPase p97 (VCP), which is mutated in various human MSP conditions. We reveal that METTL21C trimethylates p97 on the Lys315 residue and found that loss of this modification reduced p97 hexamer formation and ATPase activity in vivo. We conclude that the methyltransferase METTL21C is an important modulator of protein degradation in skeletal muscle under both normal and enhanced protein breakdown conditions. : Wiederstein et al. describe the skeletal muscle methyltransferase Mettl21c. They found that ablation of Mettl21c in mice results in muscle weakness and disturbance of the protein degradation machinery. Those changes are hallmarks of multisystem proteinopathies. They demonstrate that Mettl21c modulates p97 activity, which is frequently mutated in human patients with muscle weakness. Keywords: methyltransferases, skeletal muscle, p97, atrophy, autophagy

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