Wss1 metalloprotease partners with Cdc48/Doa1 in processing genotoxic SUMO conjugates

• DOI: 10.7554/elife.06763
• Publication Date: 2015-09-04T13:36:11Z
• Authors: Maxim Y Balakirev; James E Mullally; Adrien Favier; Nicole Assard; Eric Sulpice; David F Lindsey; Anastasia V Rulina; Xavier Gidrol; Keith D Wilkinson
• Keywords: SUMO metabolism; Saccharomyces cerevisiae Proteins; QH301-705.5; Science; DNA repair; Cell Cycle Proteins; Saccharomyces cerevisiae; Biochemistry; Cdc48; 03 medical and health sciences; Valosin Containing Protein; Doa1; [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology; Biology (General); Adaptor Proteins, Signal Transducing; Adenosine Triphosphatases; 0303 health sciences; vacuole; poly SUMO; Q; R; Sumoylation; Proteolysis; Small Ubiquitin-Related Modifier Proteins; Medicine; Mutagens

Sumoylation during genotoxic stress regulates the composition of DNA repair complexes. The yeast metalloprotease Wss1 clears chromatin-bound sumoylated proteins. Wss1 and its mammalian analog, DVC1/Spartan, belong to minigluzincins family of proteases. Wss1 proteolytic activity is regulated by a cysteine switch mechanism activated by chemical stress and/or DNA binding. Wss1 is required for cell survival following UV irradiation, the smt3-331 mutation and Camptothecin-induced formation of covalent topoisomerase 1 complexes (Top1cc). Wss1 forms a SUMO-specific ternary complex with the AAA ATPase Cdc48 and an adaptor, Doa1. Upon DNA damage Wss1/Cdc48/Doa1 is recruited to sumoylated targets and catalyzes SUMO chain extension through a newly recognized SUMO ligase activity. Activation of Wss1 results in metalloprotease self-cleavage and proteolysis of associated proteins. In cells lacking Tdp1, clearance of topoisomerase covalent complexes becomes SUMO and Wss1-dependent. Upon genotoxic stress, Wss1 is vacuolar, suggesting a link between genotoxic stress and autophagy involving the Doa1 adapter.