Evidence map›Paper›PMID 41339636›Full record

ArticleNature communications2025

The genetic and biochemical basis of human leading strand synthesis.

Alessandro Agnarelli, Lauryn Buckley-Benbow, Meryem Ozgencil, Melanie Lad, Khamal Kwesi Ampah, Alex Kalinka, Ondrej Belan, Sarah Maslen, Mark J Skehel, David Walter and 2 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

12 authors.

Alessandro Agnarelli *Centre for Cancer Cell & Molecular Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, EC1M 6BQ, London, UK.ORCID http://orcid.org/0000-0003-3218-3836
Lauryn Buckley-Benbow *Centre for Cancer Cell & Molecular Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, EC1M 6BQ, London, UK.ORCID http://orcid.org/0000-0001-5256-8632
Meryem OzgencilCentre for Cancer Cell & Molecular Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, EC1M 6BQ, London, UK.ORCID http://orcid.org/0000-0003-4685-0257
Melanie LadJoint Cancer Research Horizons-AstraZeneca Functional Genomics Centre, Biomedical Campus, 1 Francis Crick Avenue, CB2 0AA, Cambridge, UK.
Khamal Kwesi AmpahJoint Cancer Research Horizons-AstraZeneca Functional Genomics Centre, Biomedical Campus, 1 Francis Crick Avenue, CB2 0AA, Cambridge, UK.
Alex KalinkaJoint Cancer Research Horizons-AstraZeneca Functional Genomics Centre, Biomedical Campus, 1 Francis Crick Avenue, CB2 0AA, Cambridge, UK.
Ondrej BelanDivision of Genetics, Department of Medicine, Brigham and Women's Hospital and Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA.
Sarah MaslenProteomics Science Technology Platform, The Francis Crick Institute, 1 Midland Road, NW1 1AT, London, UK.
Mark J SkehelProteomics Science Technology Platform, The Francis Crick Institute, 1 Midland Road, NW1 1AT, London, UK.
David WalterJoint Cancer Research Horizons-AstraZeneca Functional Genomics Centre, Biomedical Campus, 1 Francis Crick Avenue, CB2 0AA, Cambridge, UK.ORCID http://orcid.org/0000-0003-4363-0339
Matthew DayCentre for Molecular Cell Biology, School of Biological and Behavioural Sciences, Blizard Institute, Queen Mary University of London, London, E1 2AT, UK. matthew.day@qmul.ac.uk.ORCID http://orcid.org/0000-0001-7218-867X
Roberto BellelliCentre for Cancer Cell & Molecular Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, EC1M 6BQ, London, UK. r.bellelli@qmul.ac.uk.ORCID http://orcid.org/0000-0002-2062-7113

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

The maintenance of genome stability requires efficient leading strand synthesis by DNA Polymerase Epsilon (Polε). By performing CRISPR genetic screens in cells lacking the POLE4 subunit of Polε we define a genetic map of the factors required to support Polε function in the absence of its accessory subunits. A set of genes involved in iron metabolism emerge as required to sustain Iron Sulphur Cluster (ISC)-dependent Polε activity. We then dissect a synthetic lethal interaction between POLE3-POLE4 and the CHTF18-RFC2/5 complex. By combining cell biology, structural modelling and biochemistry, we define the existence of two tiers of regulation of Polε processivity: leading strand-specific loading of PCNA by CHTF18-RFC2/5 and "gripping" of newly synthesised dsDNA by POLE3-POLE4. The combined loss of these functions is incompatible with leading strand synthesis and viability. In summary, we describe the biochemical basis of human leading strand synthesis and the consequence of its dysfunction in genome stability.

Indexed as

DNA Polymerase IIDNA ReplicationCRISPR-Cas SystemsDNAGenomic InstabilityHumansIronIron-Sulfur ProteinsProliferating Cell Nuclear AntigenDNADNA Polymerase IIIronIron-Sulfur ProteinsProliferating Cell Nuclear Antigen

Identifiers

PMID41339636
PMCPMC12796321

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.