Ctf18-RFC and DNA Pol ϵ form a stable leading strand polymerase/clamp loader complex required for normal and perturbed DNA replication
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Abstract
The eukaryotic replisome must faithfully replicate DNA and cope with replication fork blocks and stalling, while simultaneously promoting sister chromatid cohesion. Ctf18-RFC is an alternative PCNA loader that links all these processes together by an unknown mechanism. Here, we use integrative structural biology combined with yeast genetics and biochemistry to highlight the specific functions that Ctf18-RFC plays within the leading strand machinery via an interaction with the catalytic domain of DNA Pol ϵ. We show that a large and unusually flexible interface enables this interaction to occur constitutively throughout the cell cycle and regardless of whether forks are replicating or stalled. We reveal that, by being anchored to the leading strand polymerase, Ctf18-RFC can rapidly signal fork stalling to activate the S phase checkpoint. Moreover, we demonstrate that, independently of checkpoint signaling or chromosome cohesion, Ctf18-RFC functions in parallel to Chl1 and Mrc1 to protect replication forks and cell viability.
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In budding yeast, previous experiments mapped the POLD3-POLA1 interaction to the location in both proteins predicted by AF-M.
“in budding yeast, previous experiments mapped this interaction to the location in both proteins predicted by AF-M69,70.”
From Predictomes, a classifier-curated database of AlphaFold-modeled protein-protein interactions (2025) · cites this paper as [70]
The Results sections on complex architecture and recruitment to replication forks map an interaction between Pol2 (DNA polymerase ε) and Ctf18-RFC, not between POLD3 and POLA1. Searches for POLD3–POLA1 and the proposed yeast interaction found no passage in our copy addressing that interaction or its agreement with an AF-M prediction. (LLM, conf=0.74)
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Nuclear pore complexes mediate subtelomeric gene silencing by regulating PCNA levels on chromatin
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PCNA recruits cohesin loader Scc2 to ensure sister chromatid cohesion
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The Interplay of Cohesin and the Replisome at Processive and Stressed DNA Replication Forks
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Double-Stranded Break Repair in Mammalian Cells and Precise Genome Editing
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Key molecular DNA damage responses of human cells to radiation
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MMS22L-TONSL functions in sister chromatid cohesion in a pathway parallel to DSCC1-RFC
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A novel role for Dun1 in the regulation of origin firing upon hyper-acetylation of H3K56
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The cohesin complex of yeasts: sister chromatid cohesion and beyond
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Genome stability is guarded by yeast Rtt105 through multiple mechanisms
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The Fork Protection Complex: A Regulatory Hub at the Head of the Replisome
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Self-citationCompetition for the nascent leading strand shapes the requirements for PCNA loading in the replisome
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Structural and biochemical characterization of the mitomycin C repair exonuclease MrfB
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The proofreading mechanism of the human leading-strand DNA polymerase ε holoenzyme
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Draining the FEN1s for cancer therapy
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Regulation of Human DNA Primase-Polymerase PrimPol
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Structure of the human CTF18 clamp loader bound to PCNAPreprint
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- Authors
- Stokes, K., Winczura, A., Song, B., De Piccoli, G., & Grabarczyk, D. B.
- Affiliations
- University of Warwick (GB)
- University of Würzburg (DE)
- University of Warwick, Warwick Medical School, Coventry, UK
- Corresponding author
- Grabarczyk, Daniel B
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2020-06-25
- Volume
- 48
- Issue
- 14
- Pages
- 8128-8145
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- PMC
- PMC7641331
- OpenAlex
- W3037282523
- Cited by
- 48
- References
- 85
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 8 · 2023: 7 · 2022: 8 · 2021: 7 · 2020: 3
- FWCI
- 2.03
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Nucleic Acids Research (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Warwick Research Archive Portal (University of Warwick) (acceptedVersion)
- Desy Publications Database (Deutsches Elektronen-Synchrotron DESY) (submittedVersion, cc-by)
- Funders
- Cancer Research UK (C44595/A16326)
- DFG (GR 5152/3-1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- DNA polymerase epsilon, clamp loader, replisome, replication fork stalling, replication fork protection, S-phase checkpoint, sister chromatid cohesion, CHL1, CD206, DNA replication
- MeSH terms
- Replisomes, Binding Sites, DNA-Directed DNA Polymerase, DNA Replication, Multienzyme Complexes, Protein Binding, Saccharomyces cerevisiae, Cell Cycle Proteins, Saccharomyces cerevisiae Proteins
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