USP7 is essential for maintaining Rad18 stability and DNA damage tolerance.
Open accessAbstract
Rad18 functions at the cross-roads of three different DNA damage response (DDR) pathways involved in protecting stressed replication forks: homologous recombination repair, DNA inter-strand cross-link repair and DNA damage tolerance. Although Rad18 serves to facilitate replication of damaged genomes by promoting translesion synthesis (TLS), this comes at a cost of potentially error-prone lesion bypass. In contrast, loss of Rad18-dependent TLS potentiates the collapse of stalled forks and leads to incomplete genome replication. Given the pivotal nature with which Rad18 governs the fine balance between replication fidelity and genome stability, Rad18 levels and activity have a major impact on genomic integrity. Here, we identify the de-ubiquitylating enzyme USP7 as a critical regulator of Rad18 protein levels. Loss of USP7 destabilizes Rad18 and compromises UV-induced PCNA mono-ubiquitylation and Pol η recruitment to stalled replication forks. USP7-depleted cells also fail to elongate nascent daughter strand DNA following UV irradiation and show reduced DNA damage tolerance. We demonstrate that USP7 associates with Rad18 directly via a consensus USP7-binding motif and can disassemble Rad18-dependent poly-ubiquitin chains both in vitro and in vivo. Taken together, these observations identify USP7 as a novel component of the cellular DDR involved in preserving the genome stability.
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USP7 has a role in the initial stages of both translesion synthesis and template switching.
“Recent reports have suggested that USP7 has a role in the initial stages of both translesion synthesis and template switching.”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Zlatanou et al., 2016
Depleting USP7 decreases protein levels of Rad18 and HLTF, suppresses PCNA mono- and polyubiquitination, and reduces Pol η foci formation in UV irradiated cells.
“Indeed, depleting USP7 from cells was found to decrease the protein levels of Rad18 and HLTF, suppress PCNA mono and polyubiquitination, as well as reduce Pol η foci formation in UV irradiated cells.”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Zlatanou et al., 2016
USP7 indirectly influences PCNA monoubiquitination by regulating the stability of Rad18 and HLTF E3 ubiquitin ligases.
“In addition, USP7 has been suggested to indirectly influence PCNA mono-ubiqutination, by regulating the stability of the Rad18 and HLTF E3 ubiquitin ligases (Qing et al., 2011; Zlatanou et al., 2016).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Zlatanou et al., 2016
Pol η protein levels appeared unchanged following siRNA-mediated depletion of USP7 in a subsequent publication.
“It should be noted, however, that despite the attractive elegance of this proposed model, these claims have been contradicted by a subsequent publication, where Pol η protein levels appeared unchanged following siRNA-mediated depletion of USP7 (Zlatanou et al., 2016).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Zlatanou et al., 2016
Following UV exposure, cells depleted of USP7 are defective at elongating nascent DNA strands.
“Indeed, following UV exposure, cells depleted of USP7 are defective at elongating nascent DNA strands (Zlatanou et al., 2016).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Zlatanou et al., 2016
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- Authors
- Zlatanou, A., Sabbioneda, S., Miller, E. S., Greenwalt, A., Aggathanggelou, A., Maurice, M. M., Lehmann, A. R., Stankovic, T., Reverdy, C., Colland, F., Vaziri, C., & Stewart, G. S.
- Affiliations
- University of Birmingham (GB)
- Istituto di Genetica Molecolare (IT)
- University of North Carolina at Chapel Hill (US)
- University Medical Center Utrecht (NL)
- University of Sussex (GB)
- Hybrigenics (France) (FR)
- Corresponding author
- Stewart, G S
- Venue
- Oncogene
- Published
- 2015-05-11
- Volume
- 35
- Issue
- 8
- Pages
- 965-976
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W212561335
- Cited by
- 77
- References
- 54
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 5 · 2023: 10 · 2022: 2 · 2021: 4 · 2020: 14 · 2019: 13 · 2018: 3 · 2017: 10 · 2016: 8 · 2015: 3
- FWCI
- 3.47
- Type
- journal article
- Language
- en
- Open access
- green
- dspace.library.uu.nl
- Licence
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Funders
- Cancer Research UK (C17183/A13030)
- National Cancer Institute (F31CA177179)
- National Institute of Environmental Health Sciences (R01ES009558)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- USP7, RAD18, DNA damage tolerance, DNA damage response, translesion synthesis, stalled replication forks, UV-induced DNA damage, genome stability
- MeSH terms
- Ubiquitin-Specific Peptidase 7, Cell Line, DNA Damage, DNA Repair, DNA-Binding Proteins, HeLa Cells, Humans, Protein Binding, Amino Acid Motifs, Ubiquitin, Ubiquitin Thiolesterase, Ubiquitin-Protein Ligases, Protein Stability
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