Ubiquitin chain editing promotes p97/VCP dependent removal of RPA from DNA

Here, we show how error-free DNA repair is controlled by a ubiquitin-dependent mechanism. Central to this is a multi-component ubiquitin chain editing complex, consisting at its core of the single-stranded DNA (ssDNA) binding RPA complex and the ZUP1 deubiquitinase.

We show that RPA activates the ZUP1 deubiquitinase towards K63-linkages within diverse ubiquitin chain types and couples this activity to DNA damage recognition. Coupling of these activities is important to control the ubiquitination status of key DNA repair substrates, which allows the RPA-ZUP1 ubiquitin chain editing complex both to balance the usage of error-free DNA repair pathways and prevent toxic protein trapping on DNA.