2. Academic Validation
  3. USP7 and VCPFAF1 define the SUMO/Ubiquitin landscape at the DNA replication fork

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

  • Cell Rep. 2021 Oct 12;37(2):109819. doi: 10.1016/j.celrep.2021.109819.
André Franz 1,  Pablo Valledor 2,  Patricia Ubieto-Capella 2,  Domenic Pilger 3,  Antonio Galarreta 2,  Vanesa Lafarga 2,  Alejandro Fernández-Llorente 4,  Guillermo de la Vega-Barranco 4,  Fabian den Brave 5,  Thorsten Hoppe 6,  Oscar Fernandez-Capetillo 7,  Emilio Lecona 8
Affiliations

Affiliations

  • 1 Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.
  • 2 Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
  • 3 The Wellcome Trust and Cancer Research UK Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, UK.
  • 4 Chromatin, Cancer and the Ubiquitin System lab, Centre for Molecular Biology Severo Ochoa (CBMSO, CSIC-UAM), Department of Genome Dynamics and Function, Madrid 28049, Spain.
  • 5 Institute of Biochemistry and Molecular Biology, University of Bonn, 53115 Bonn, Germany.
  • 6 Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany. Electronic address: [email protected].
  • 7 Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain; Science for Life Laboratory, Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 21 Stockholm, Sweden. Electronic address: [email protected].
  • 8 Chromatin, Cancer and the Ubiquitin System lab, Centre for Molecular Biology Severo Ochoa (CBMSO, CSIC-UAM), Department of Genome Dynamics and Function, Madrid 28049, Spain. Electronic address: [email protected].
PMID: 34644576 DOI: 10.1016/j.celrep.2021.109819
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.

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