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.

We report a one-pot, three-component synthesis of sulfides by exploiting a sulfoxide reagent as a formal sulfur dication equivalent. Our protocol consists of three simple chemical operations involving two Grignard reagents and trimethylsilyl chloride (TMSCl) to sequentially form sulfenate anions, sulfenate esters, and sulfides. We demonstrate a wide range of Grignard reagents to be coupled, thereby allowing the modular, thiol-free synthesis of sulfides including dialkenyl and alkenyl–alkynyl sulfides.

Sulfides are prevalent in bioactive molecules and have also found numerous applications in synthesis. Various reagents have been developed for the three-component synthesis of sulfides, but the strategic use of sulfur dication equivalents for this purpose has been largely overlooked. Here we report a one-pot, three-component synthesis of sulfides exploiting a sulfoxide reagent as a formal sulfur dication equivalent, unlocking new synthetic chemistry of sulfenate anions. Our protocol involves three chemical operations to sequentially form sulfenate anions, sulfenate esters, and sulfides, using two Grignard reagents and trimethylsilyl chloride (TMSCl). We demonstrate a wide range of Grignard reagents to be coupled, thereby allowing the modular synthesis of sulfides, including dialkenyl and alkenyl-alkynyl sulfides.