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USP7 and VCPFAF1 define the SUMO/Ubiquitin landscape at DNA replication forks

ABSTRACT: The AAA+ ATPase VCP regulates the extraction of SUMO and/or ubiquitin modified factors from chromatin. We previously showed that active DNA synthesis is associated with a SUMO-high and ubiquitin-low environment that is maintained by the deubiquitylase USP7. Here we unveil a functional cooperation between USP7 and VCP in the control of DNA replication conserved from Caenorhabditis elegans to mammals. The function of VCP during DNA replication is mediated by its cofactor FAF1, which facilitates the extraction of SUMOylated proteins that accumulate on chromatin upon USP7 inhibition. Supporting this cooperative role, the inactivation of the orthologues of USP7 and FAF1 is synthetic lethal in C. elegans, and USP7 and FAF1 inhibitors display synergistic toxicity. Together, these results reveal a coordinated activity of USP7 and VCPFAF1 in limiting SUMOylation at active replication forks and promoting the extraction and degradation of ubiquitylated proteins.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Eduardo Zarzuela

LAB HEAD: Javier Muñoz

PROVIDER: PXD018623 | Pride | 2021-09-12

REPOSITORIES: Pride

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