RRC ID 75960
Author Franz A, Valledor P, Ubieto-Capella P, Pilger D, Galarreta A, Lafarga V, Fernández-Llorente A, de la Vega-Barranco G, den Brave F, Hoppe T, Fernandez-Capetillo O, Lecona E.
Title USP7 and VCPFAF1 define the SUMO/Ubiquitin landscape at the DNA replication fork.
Journal Cell Rep
Abstract The AAA+ ATPase VCP regulates the extraction of SUMO and ubiquitin-modified DNA replication factors from chromatin. We have previously described that active DNA synthesis is associated with a SUMO-high/ubiquitin-low environment governed by the deubiquitylase USP7. Here, we unveil a functional cooperation between USP7 and VCP in DNA replication, which is conserved from Caenorhabditis elegans to mammals. The role of VCP in chromatin is defined by its cofactor FAF1, which facilitates the extraction of SUMOylated and ubiquitylated proteins that accumulate after the block of DNA replication in the absence of USP7. The inactivation of USP7 and FAF1 is synthetically lethal both in C. elegans and mammalian cells. In addition, USP7 and VCP inhibitors display synergistic toxicity supporting a functional link between deubiquitylation and extraction of chromatin-bound proteins. Our results suggest that USP7 and VCPFAF1 facilitate DNA replication by controlling the balance of SUMO/Ubiquitin-modified DNA replication factors on chromatin.
Volume 37(2)
Pages 109819
Published 2021-10-12
DOI 10.1016/j.celrep.2021.109819
PII S2211-1247(21)01283-3
PMID 34644576
PMC PMC8527565
MeSH Adaptor Proteins, Signal Transducing / genetics Adaptor Proteins, Signal Transducing / metabolism* Animals Animals, Genetically Modified Apoptosis Regulatory Proteins / genetics Apoptosis Regulatory Proteins / metabolism* Caenorhabditis elegans / genetics Caenorhabditis elegans / metabolism Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism Carrier Proteins / genetics Carrier Proteins / metabolism Chromatin / genetics Chromatin / metabolism* DNA Replication* Endopeptidases / genetics Endopeptidases / metabolism Evolution, Molecular HCT116 Cells HeLa Cells Humans MCF-7 Cells Sumoylation Ubiquitin-Specific Peptidase 7 / genetics Ubiquitin-Specific Peptidase 7 / metabolism* Ubiquitination* Valosin Containing Protein / genetics Valosin Containing Protein / metabolism*
C.elegans tm6658 tm544 tm6724