Function and evolution of the DNA-protein crosslink proteases Wss1 and SPRTN

Covalent DNA-protein crosslinks (DPCs) are highly toxic DNA adducts, which interfere with faithful DNA replication. The proteases Wss1 and SPRTN degrade DPCs and have emerged as crucially important DNA repair enzymes. Their protective role has been described in various model systems ranging from yeasts, plants, worms and flies to mice and humans. Loss of DPC proteases results in genome instability, cellular arrest, premature ageing and cancer predisposition. Here we discuss recent insights into the function and molecular mechanism of these enzymes. Furthermore, we present an in-depth phylogenetic analysis of the Wss1/SPRTN protease continuum. Remarkably flexible domain architectures and constantly changing protein-protein interaction motifs indicate ongoing evolutionary dynamics. Finally, we discuss recent data, which suggest that further partially-overlapping proteolytic systems targeting DPCs exist in eukaryotes. These new developments raise interesting questions regarding the division of labour between different DPC proteases and the mechanisms and principles of repair pathway choice.