ArticleScience advances2025
Mechanism of DNA replication fork breakage and PARP1 hyperactivation during replication catastrophe.
Article in Science advances, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed.
- PARG inhibition reduces ssDNA levels and limits RPA loading upon replication fork collapse.EMBO reports · 2026Article
- Collapsing retroviruses for efficient delivery of viro-toxic cargoes.bioRxiv : the preprint server for biology · 2026Article
- Tilting the balance of life and death: navigating DNA replication stress in cancer therapy.Experimental & molecular medicine · 2026Review
- Distinct repair outcomes from single and convergent replication fork collapse.Nature structural & molecular biology · 2026Article
- Squamous-state excursions activate APOBEC3A in cancer.bioRxiv : the preprint server for biology · 2026Article
- Increased replication-associated single-stranded DNA promotes formaldehyde-induced mutagenesis.bioRxiv : the preprint server for biology · 2026Article
- Targeted inhibition of PARP-1 in pulmonary epithelial cells and macrophages via SPA-functionalized microparticles attenuates sepsis-induced lung injury.Materials today. Bio · 2026Article
- Interplay Between Poly(ADP-ribosyl)ation and Specific Inner Cellular Events That Suggest Combination Strategies for Overcoming PARP Inhibitor Resistance.Pharmaceutics · 2026Review
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- The expanding roles of homologous recombination proteins in genome stability.The EMBO journal · 2026Review
- Dynamic Assemblies in Genome Maintenance.Advances in experimental medicine and biology · 2026Review
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- Replication-associated base excision repair/single-strand break repair regulates PARG inhibitor response via the PRMT1/PRMT5/ATR axis.NAR cancer · 2025Article
- BRCA2 deficiency and replication stress drive APOBEC3-Mediated genomic instability.Nature communications · 2025Article
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Authors and funding
10 authors.
Funding
Abstract
Ataxia telangiectasia and Rad3-related (ATR) inhibition triggers a surge in origin firing, resulting in increased levels of single-stranded DNA (ssDNA) that rapidly deplete all available RPA. This leaves ssDNA unprotected and susceptible to breakage, a phenomenon known as replication catastrophe. However, the mechanism by which unprotected ssDNA breaks remains unclear. Here, we reveal that APOBEC3B is the key enzyme targeting unprotected ssDNA at replication forks, initiating a reaction cascade that induces fork collapse and poly(ADP-ribose) polymerase 1 (PARP1) hyperactivation. Mechanistically, we demonstrate that uracils generated by APOBEC3B at replication forks are removed by UNG2, resulting in abasic sites that are subsequently cleaved by APE1 endonuclease. Moreover, we show that APE1-mediated DNA cleavage is the critical enzymatic step for PARP1 hyperactivation in cells, regardless of how abasic sites are generated on DNA. Last, we demonstrate that APOBEC3B-induced PARP1 trapping and DNA double-strand breaks drive cell sensitivity to ATR inhibition, creating a context of synthetic lethality when coupled with PARP inhibitors.
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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.