Replication fork slowing and reversal upon DNA damage require PCNA polyubiquitination and ZRANB3 DNA translocase activity.
Open accessAbstract
DNA damage tolerance during eukaryotic replication is orchestrated by PCNA ubiquitination. While monoubiquitination activates mutagenic translesion synthesis, polyubiquitination activates an error-free pathway, elusive in mammals, enabling damage bypass by template switching. Fork reversal is driven in vitro by multiple enzymes, including the DNA translocase ZRANB3, shown to bind polyubiquitinated PCNA. However, whether this interaction promotes fork remodeling and template switching in vivo was unknown. Here we show that damage-induced fork reversal in mammalian cells requires PCNA ubiquitination, UBC13, and K63-linked polyubiquitin chains, previously involved in error-free damage tolerance. Fork reversal in vivo also requires ZRANB3 translocase activity and its interaction with polyubiquitinated PCNA, pinpointing ZRANB3 as a key effector of error-free DNA damage tolerance. Mutations affecting fork reversal also induced unrestrained fork progression and chromosomal breakage, suggesting fork remodeling as a global fork slowing and protection mechanism. Targeting these fork protection systems represents a promising strategy to potentiate cancer chemotherapy.
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K63-linked polyubiquitination of PCNA stimulates template switching by creating a binding platform for ZRANB3.
“Recently, K63-linked polyubiquitination of PCNA was found to stimulate template switching by creating a binding platform for the DNA translocase, ZRANB3 (Vujanovic et al., 2017).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Vujanovic et al., 2017
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CHK1 phosphorylates PRIMPOL to promote replication stress tolerance
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Self-citationResistance to PARP Inhibitors: Lessons from Preclinical Models of BRCA-Associated Cancer
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Revisiting the BRCA-pathway through the lens of replication gap suppression
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PCNA Loaders and Unloaders—One Ring That Rules Them All
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Mechanisms and regulation of replication fork reversal
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Self-citationUbe2V2 Is a Rosetta Stone Bridging Redox and Ubiquitin Codes, Coordinating DNA Damage Responses
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The MCM8/9 complex: A recent recruit to the roster of helicases involved in genome maintenance
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SLX4: multitasking to maintain genome stability
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ATAD5 promotes replication restart by regulating RAD51 and PCNA in response to replication stress
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DNA-PKcs promotes fork reversal and chemoresistance
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Self-citationRemoval of RTF2 from Stalled Replisomes Promotes Maintenance of Genome Integrity
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Replication Fork Reversal and Protection
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Self-citationEukaryotic clamp loaders and unloaders in the maintenance of genome stability
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Dhoonmoon, A., Nicolae, C. M., & Moldovan, G. (2022) · Nature Communications · doi:10.1038/s41467-022-32756-5 · Cited by 47 · see citing works
Boleslavska, B., Oravetzova, A., Shukla, K., Naščáková, Z., Ibini, O., Hašanová, Z., Andrš, M., Kanagaraj, R., Dobrovolná, J., & Janščák, P. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkac1116 · Cited by 48 · see citing works
Freedom to err: The expanding cellular functions of translesion DNA polymerases.
Paniagua, I., & Jacobs, J. (2023) · Molecules and Cells · doi:10.1016/j.molcel.2023.07.008 · Cited by 44 · see citing works
Time for remodeling: SNF2-family DNA translocases in replication fork metabolism and human disease
Joseph, S. A., Taglialatela, A., Leuzzi, G., Huang, J., Cuella-Martin, R., & Ciccia, A. (2020) · DNA repair · doi:10.1016/j.dnarep.2020.102943 · Cited by 47 · see citing works
Self-citationDNA-damage tolerance through PCNA ubiquitination and sumoylation
Fan, L., Bi, T., Wang, L., & Xiao, W. (2020) · Biochemical Journal · doi:10.1042/bcj20190579 · Cited by 40 · see citing works
Zhang, J., Bellani, M., James, R., Pokharel, D., Zhang, Y.-Q., Reynolds, J., McNee, G. S., Jackson, A., Stewart, G., & Seidman, M. (2020) · Nature Communications · doi:10.1038/s41467-020-17449-1 · Cited by 39 · see citing works
Homologous Recombination as a Fundamental Genome Surveillance Mechanism during DNA Replication
Spies, J., Polášek-Sedláčková, H., Lukas, J., & Somyajit, K. (2021) · Genes · doi:10.3390/genes12121960 · Cited by 43 · see citing works
Wong, R. P. C., Petriukov, K. S., & Ulrich, H. D. (2021) · DNA repair · doi:10.1016/j.dnarep.2021.103163 · Cited by 40 · see citing works
Beyond Kinases: Targeting Replication Stress Proteins in Cancer Therapy
Baillie, K. E., & Stirling, P. C. (2020) · Trends in cancer · doi:10.1016/j.trecan.2020.10.010 · Cited by 40 · see citing works
CDC7 kinase promotes MRE11 fork processing, modulating fork speed and chromosomal breakage
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Self-citationThe Replication Stress Response on a Narrow Path Between Genomic Instability and Inflammation
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Self-citationPCNA cycling dynamics during DNA replication and repair in mammals
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DNA Damage Tolerance Pathways in Human Cells: A Potential Therapeutic Target
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Replication stress at microsatellites causes DNA double-strand breaks and break-induced replication
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Stress-triggered hematopoietic stem cell proliferation relies on PrimPol-mediated repriming
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Self-citationLooping out of control: R-loops in transcription-replication conflict
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Smarcal1 and Zranb3 Protect Replication Forks from Myc-Induced DNA Replication Stress
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WRNIP1 Protects Reversed DNA Replication Forks from SLX4-Dependent Nucleolytic Cleavage
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Mechanisms of direct replication restart at stressed replisomes
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Replication fork uncoupling causes nascent strand degradation and fork reversal
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Self-citationEmerging functions of Fanconi anemia genes in replication fork protection pathways
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Role of Translesion DNA Synthesis in the Metabolism of Replication-associated Nascent Strand Gaps
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Cavin3 released from caveolae interacts with BRCA1 to regulate the cellular stress response
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The levels of p53 govern the hierarchy of DNA damage tolerance pathway usage
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Replication Fork Remodeling and Therapy Escape in DNA Damage Response-Deficient Cancers
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Ubiquitylation at Stressed Replication Forks: Mechanisms and Functions
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Critical DNA damaging pathways in tumorigenesis
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- Authors
- Vujanovic, M., Krietsch, J., Raso, M. C., Terraneo, N., Zellweger, R., Schmid, J. A., Taglialatela, A., Huang, J.-W., Holland, C. L., Zwicky, K., Herrador, R., Jacobs, H., Cortez, D., Ciccia, A., Penengo, L., & Lopes, M.
- Affiliations
- University of Zurich (CH)
- Columbia University Irving Medical Center (US)
- Vanderbilt University (US)
- The Netherlands Cancer Institute (NL)
- Corresponding author
- Lopes, Massimo
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2017-09
- Volume
- 67
- Issue
- 5
- Pages
- 882-890.e5
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC5594246
- OpenAlex
- W2751450140
- Cited by
- 227
- References
- 39
- Citations by year
- 2026: 10 · 2025: 19 · 2024: 25 · 2023: 27 · 2022: 23 · 2021: 28 · 2020: 35 · 2019: 26 · 2018: 27 · 2017: 7
- FWCI
- 10.62
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DORA PSI (Paul Scherrer Institute) (submittedVersion, cc-by-nc-nd)
- Funders
- SNF (31003A_146924, 31003A_169959, 31003A_166370)
- ERC Consolidator (617102)
- Helmut Horten
- NIH (R01CA197774, GM116616)
- KWF (NKI-2012-5243)
- ZonMW Top (91213018)
- 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
- replication fork reversal, DNA damage tolerance, ZRANB3, DNA translocase, Ubc13, K63-linked polyubiquitin, template switching, chromosome breakage, cancer chemotherapy
- MeSH terms
- Animals, DNA Damage, DNA Replication, DNA Helicases, DNA, Neoplasm, Humans, Kinetics, Mutation, Neoplasms, Transfection, Replication Origin, Proliferating Cell Nuclear Antigen, Polyubiquitin, RNA Interference, Ubiquitin-Conjugating Enzymes, HCT116 Cells, Mice, Ubiquitination, HEK293 Cells, CRISPR-Cas Systems
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