ArticleNucleic acids research2024
The loss of DNA polymerase epsilon accessory subunits POLE3-POLE4 leads to BRCA1-independent PARP inhibitor sensitivity.
Article in Nucleic acids research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- Loss of CHTF18-RFC2/5 leads to replicative gaps and sensitivity to PARP inhibitors.NAR cancer · 2026Article
- Replication protein A protects lagging strand gaps, restricting PARP inhibitor-induced synthetic lethality in BRCA1-deficient tumors.Nucleic acids research · 2026Article
- Functional Characterization ofDiseases (Basel, Switzerland) · 2026Article
- DRESIS 2.0: the comprehensive landscape of drug resistance information.Nucleic acids research · 2026Article
- Integrative proteomics reveals MSH6 to modulate PARP inhibitor sensitivity in BRCA1/2-proficient ovarian cancer.PloS one · 2026Article
- The genetic and biochemical basis of human leading strand synthesis.Nature communications · 2025Article
- Pamoic acid and carbenoxolone specifically inhibit CRISPR/Cas9 in bacteria, mammalian cells, and mice in a DNA topology-specific manner.Genome biology · 2025Article
- 'Where is my gap': mechanisms underpinning PARP inhibitor sensitivity in cancer.Biochemical Society transactions · 2025Review
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Authors and funding
15 authors.
Funding
Abstract
The clinical success of PARP1/2 inhibitors (PARPi) prompts the expansion of their applicability beyond homologous recombination deficiency. Here, we demonstrate that the loss of the accessory subunits of DNA polymerase epsilon, POLE3 and POLE4, sensitizes cells to PARPi. We show that the sensitivity of POLE4 knockouts is not due to compromised response to DNA damage or homologous recombination deficiency. Instead, POLE4 loss affects replication speed leading to the accumulation of single-stranded DNA gaps behind replication forks upon PARPi treatment, due to impaired post-replicative repair. POLE4 knockouts elicit elevated replication stress signaling involving ATR and DNA-PK. We find POLE4 to act parallel to BRCA1 in inducing sensitivity to PARPi and counteracts acquired resistance associated with restoration of homologous recombination. Altogether, our findings establish POLE4 as a promising target to improve PARPi driven therapies and hamper acquired PARPi resistance.
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