Evidence map›Paper›PMID 41006228›Full record

ArticleNature communications2025

EXO1 as a therapeutic target for Fanconi Anaemia, ZRSR2 and BRCA1-A complex deficient cancers.

Marija Maric, Sandra Segura-Bayona, Raviprasad Kuthethur, Tohru Takaki, Valerie Borel, Tyler H Stanage, Miroslav P Ivanov, Nishita Parnandi, Graeme Hewitt, Rhona Millar and 8 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. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing 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

0 citing papers in PubMed.

No citing paper in PubMed yet.

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

18 authors.

Marija MaricDSB Repair Metabolism Laboratory, The Francis Crick Institute, London, UK.ORCID http://orcid.org/0000-0001-7780-0442
Sandra Segura-BayonaDSB Repair Metabolism Laboratory, The Francis Crick Institute, London, UK.ORCID http://orcid.org/0000-0001-7788-9889
Raviprasad KuthethurDepartment of Molecular Genetics, Erasmus Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.ORCID http://orcid.org/0000-0003-0697-7835
Tohru TakakiDSB Repair Metabolism Laboratory, The Francis Crick Institute, London, UK.
Valerie BorelDSB Repair Metabolism Laboratory, The Francis Crick Institute, London, UK.
Tyler H StanageDSB Repair Metabolism Laboratory, The Francis Crick Institute, London, UK.ORCID http://orcid.org/0000-0003-1668-9909
Miroslav P IvanovDSB Repair Metabolism Laboratory, The Francis Crick Institute, London, UK.ORCID http://orcid.org/0000-0001-9352-0969
Nishita ParnandiDSB Repair Metabolism Laboratory, The Francis Crick Institute, London, UK.
Graeme HewittDSB Repair Metabolism Laboratory, The Francis Crick Institute, London, UK.
Rhona MillarDSB Repair Metabolism Laboratory, The Francis Crick Institute, London, UK.
Carmen S FonsecaDepartment of Molecular Genetics, Erasmus Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
Harshil PatelBioinformatics and Biostatistics Facility, The Francis Crick Institute, London, UK.ORCID http://orcid.org/0000-0003-2707-7940
Miriam LlorianBioinformatics and Biostatistics Facility, The Francis Crick Institute, London, UK.ORCID http://orcid.org/0000-0003-2582-6602
Scott WarchalHigh Throughput Screening Facility, The Francis Crick Institute, London, UK.
Michael HowellHigh Throughput Screening Facility, The Francis Crick Institute, London, UK.ORCID http://orcid.org/0000-0003-0912-0079
Arnab Ray ChaudhuriDepartment of Molecular Genetics, Erasmus Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
Panagiotis KotsantisDSB Repair Metabolism Laboratory, The Francis Crick Institute, London, UK.ORCID http://orcid.org/0000-0002-6131-4009
Simon J BoultonDSB Repair Metabolism Laboratory, The Francis Crick Institute, London, UK. simon.boulton@crick.ac.uk.ORCID http://orcid.org/0000-0001-6936-6834

Funding

Wellcome Trust CC2057
6 · The paper itself

Abstract

Exonuclease EXO1 performs multiple roles in DNA replication and DNA damage repair (DDR). However, EXO1 loss is well-tolerated, suggesting the existence of compensatory mechanisms that could be exploited in DDR-deficient cancers. Using CRISPR screening, we find EXO1 loss as synthetic lethal with many DDR genes somatically inactivated in cancers, including Fanconi Anaemia (FA) pathway and BRCA1-A complex genes. We also identify the spliceosome factor and tumour suppressor ZRSR2 as synthetic lethal with loss of EXO1 and show that ZRSR2-deficient cells are attenuated for FA pathway activation, exhibiting cisplatin sensitivity and radial chromosome formation. Furthermore, FA or ZRSR2 deficiencies depend on EXO1 nuclease activity and can be potentiated in combination with PARP inhibitors or ionizing radiation. Finally, we uncover dysregulated replication-coupled repair as the driver of synthetic lethality between EXO1 and FA pathway attributable to defective fork reversal, elevated replication fork speeds, post-replicative single stranded DNA exposure and DNA damage. These findings implicate EXO1 as a synthetic lethal vulnerability and promising drug target in a broad spectrum of DDR-deficient cancers unaddressed by current therapies.

Indexed as

BRCA1 ProteinDNA Repair EnzymesExodeoxyribonucleasesFanconi AnemiaNeoplasmsCell Line, TumorCisplatinCRISPR-Cas SystemsDNA DamageDNA RepairDNA ReplicationHumansPoly(ADP-ribose) Polymerase InhibitorsSynthetic Lethal MutationsBRCA1 ProteinBRCA1 protein, humanCisplatinDNA Repair EnzymesEXO1 protein, humanExodeoxyribonucleasesPoly(ADP-ribose) Polymerase Inhibitors

Identifiers

PMID41006228
PMCPMC12475092

What Socratic holds

Textmetadata
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 Socratic graph.