Repair switches

Mol. Cell (2020)

DNA–protein crosslinks (DPCs) impede regular cellular processes, including DNA duplication and transcription, and induce genome instability. SPRTN is a DNA-dependent metalloprotease that translocates to the chromatin to repair DPCs when monoubiquitin is removed. However, the identities of the enzymes that remove ubiquitin were not known. By screening a panel of deubiquitinating enzymes (DUBs), followed by biochemical characterization and mutagenesis, Huang et al. identified VCPIP1 as a DUB of SPRTN that directly binds to ubiquitinated SPRTN and recruits acetylation enzymes. Acetylation of SPRTN is essential for promoting chromatin translocation of SPRTN and the subsequent DPC repair. Knockdown of VCPIP1 or replacement of the wild type with a catalytic inactive mutant decreases SPRTN acetylation, suppresses the chromatin translocation of SPRTN, and increases DPC accumulation and sensitivity to DPC-inducing agents. The DUB activity of VCPIP1 is dependent on its phosphorylation, which is mediated by DNA-damage-responsive kinases upon DPC induction. This study depicts a detailed early picture of DPC repair and promotes an understanding of the concerted regulatory roles of PTMs in controlling protein activities.

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Correspondence to Yiyun Song.

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Song, Y. Repair switches. Nat Chem Biol 16, 933 (2020).

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