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.
Keywords:
CDC-48; DNA replication; DUB; FAF1; MATH-33; SUMO; UBXN-3; USP7; VCP; ubiquitin.
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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Animals, Genetically Modified
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism*
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Caenorhabditis elegans / genetics
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Caenorhabditis elegans / metabolism
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Caenorhabditis elegans Proteins / genetics
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Caenorhabditis elegans Proteins / metabolism
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Chromatin / genetics
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Chromatin / metabolism*
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DNA Replication*
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Endopeptidases / genetics
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Endopeptidases / metabolism
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Evolution, Molecular
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HCT116 Cells
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HeLa Cells
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Humans
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MCF-7 Cells
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Sumoylation
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Ubiquitin-Specific Peptidase 7 / genetics
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Ubiquitin-Specific Peptidase 7 / metabolism*
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Ubiquitination*
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Valosin Containing Protein / genetics
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Valosin Containing Protein / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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Apoptosis Regulatory Proteins
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Caenorhabditis elegans Proteins
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Carrier Proteins
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Chromatin
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FAF1 protein, human
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UBXN-3 protein, C elegans
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Endopeptidases
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MATH-33 protein, C elegans
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USP7 protein, human
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Ubiquitin-Specific Peptidase 7
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VCP protein, human
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Valosin Containing Protein
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cdc-48.1 protein, C elegans