Evidence map›Paper›PMID 35649380›Full record

ArticleCell reports2022

Disrupted control of origin activation compromises genome integrity upon destabilization of Polε and dysfunction of the TRP53-CDKN1A/P21 axis.

Valerie Borel, Stefan Boeing, Niek Van Wietmarschen, Sriram Sridharan, Bethany Rebekah Hill, Luigi Ombrato, Jimena Perez-Lloret, Deb Jackson, Robert Goldstone, Simon J Boulton and 2 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell reports, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing papers in PubMed
0.7field-weighted citation impact, top 28% of its field
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

4 citing papers in PubMed, 7 citations in OpenAlex.

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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 at 3 institutions in 2 countries.

Valerie BorelThe Francis Crick Institute, 1 Midland Road, NW1 1AT London, UK.
Stefan BoeingThe Francis Crick Institute, 1 Midland Road, NW1 1AT London, UK.
Niek Van WietmarschenLaboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, MD, USA.
Sriram SridharanLaboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, MD, USA.
Bethany Rebekah HillCentre for Cancer Cell and Molecular Biology, The Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, Barbican, EC1M 6BE London, UK.
Luigi OmbratoCentre for Tumour Microenvironment, The Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, Barbican, EC1M 6BE London, UK.
Jimena Perez-LloretThe Francis Crick Institute, 1 Midland Road, NW1 1AT London, UK.
Deb JacksonThe Francis Crick Institute, 1 Midland Road, NW1 1AT London, UK.
Robert GoldstoneThe Francis Crick Institute, 1 Midland Road, NW1 1AT London, UK.
Simon J BoultonThe Francis Crick Institute, 1 Midland Road, NW1 1AT London, UK.
Andre NussenzweigLaboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, MD, USA.
Roberto BellelliCentre for Cancer Cell and Molecular Biology, The Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, Barbican, EC1M 6BE London, UK. Electronic address: r.bellelli@qmul.ac.uk.
The Francis Crick Institute · GBNational Human Genome Research Institute · USQueen Mary University of London · GB

Funding

DNA RepairZIABC010283 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI NUSSENZWEIG, ANDRE A. · 2009 to 2025
$27.0M
Relationship between DNA damage detection and signalingZIABC010959 · NCI · DIVISION OF BASIC SCIENCES - NCI · PI NUSSENZWEIG, ANDRE A. · 2009 to 2025
$27.0M
Cancer Research UK 28990Cancer Research UK C7893/A26233Cancer Research UK FC0010048Medical Research Council FC0010048Wellcome Trust
6 · The paper itself

Abstract

The maintenance of genome stability relies on coordinated control of origin activation and replication fork progression. How the interplay between these processes influences human genetic disease and cancer remains incompletely characterized. Here we show that mouse cells featuring Polε instability exhibit impaired genome-wide activation of DNA replication origins, in an origin-location-independent manner. Strikingly, Trp53 ablation in primary Polε hypomorphic cells increased Polε levels and origin activation and reduced DNA damage in a transcription-dependent manner. Transcriptome analysis of primary Trp53 knockout cells revealed that the TRP53-CDKN1A/P21 axis maintains appropriate levels of replication factors and CDK activity during unchallenged S phase. Loss of this control mechanism deregulates origin activation and perturbs genome-wide replication fork progression. Thus, while our data support an impaired origin activation model for genetic diseases affecting CMG formation, we propose that loss of the TRP53-CDKN1A/P21 tumor suppressor axis induces inappropriate origin activation and deregulates genome-wide fork progression.

Indexed as

Cyclin-Dependent Kinase Inhibitor p21DNA Polymerase IIDNA ReplicationPoly-ADP-Ribose Binding ProteinsReplication OriginTumor Suppressor Protein p53AnimalsCell Cycle ProteinsDNA DamageMiceS PhaseCdkn1a protein, mouseCell Cycle ProteinsCyclin-Dependent Kinase Inhibitor p21DNA Polymerase IIPole protein, mousePoly-ADP-Ribose Binding ProteinsTrp53 protein, mouseTumor Suppressor Protein p53CDKN1A/P21CP: Molecular biologyDNA replicationgenome stabilityPolεTRP53

Identifiers

PMID35649380
PMCPMC9637995
OpenAlexW4281678169

What OpenQuestion holds

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LicenceCC BY
Read underepoch 390

Registered trials

None linked

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.