Repair of covalent DNA-protein crosslinks (DPCs) by the metalloprotease SPRTN 
prevents genome instability, premature aging and carcinogenesis. SPRTN is 
specifically activated by DNA structures containing single- and double-stranded 
features, but degrades the protein components of DPCs promiscuously and 
independent of amino acid sequence. This lack of specificity is useful to target 
diverse protein adducts, however, it requires tight control in return, in order 
to prohibit uncontrolled proteolysis of chromatin proteins. Here, we discover 
the components and principles of a ubiquitin switch, which negatively regulates 
SPRTN. We demonstrate that monoubiquitylation is induced in an E3 
ligase-independent manner and, in contrast to previous assumptions, does not 
control chromatin access of the enzyme. Data obtained in cells and in vitro 
reveal that monoubiquitylation induces inactivation of the enzyme by triggering 
autocatalytic cleavage in trans while also priming SPRTN for proteasomal 
degradation in cis. Finally, we show that the deubiquitylating enzyme USP7 
antagonizes this negative control of SPRTN in the presence of DPCs.