ArticleNucleic acids research2024
USP1-dependent nucleolytic expansion of PRIMPOL-generated nascent DNA strand discontinuities during replication stress.
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 21 papers.
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Who cites it
21 citing papers in PubMed, 25 citations in OpenAlex.
- A system-level metastable model of cancer evolution: integrating replication stress, cell cycle deregulation and chromosomal instability.Annals of medicine · 2026Review
- TET2 loss triggers ssDNA gap accumulation and heightened PARP inhibitor sensitivity.Nature communications · 2026Article
- USP1 inhibition promotes RAD18-dependent PCNA degradation and BRCA1 synthetic lethality.bioRxiv : the preprint server for biology · 2026Article
- LIPT1 loss confers replication stress and PARP inhibitor sensitivity through PrimPol-mediated ssDNA gaps.Science advances · 2026Article
- Understanding single stranded DNA gaps: from formation to fate.The Biochemical journal · 2026Review
- The nuclease EXO1 promotes genomic instability by degrading nascent DNA in BRCA-proficient cells.Nature communications · 2026Article
- Genome-wide CRISPR screens identify the EXO1-CAF-1 pathway suppressing R-loop-associated DNA damage.Nucleic acids research · 2026Article
- Article
- The DNA-PKcs/JNK/p53 pathway underlies changes in cell fate decision toward death during DNA replication catastrophe.Nucleic acids research · 2025Article
- MRN-CtIP, EXO1, and DNA2-WRN/BLM act bidirectionally to process DNA gaps in PARPi-treated cells without strand cleavage.Genes & development · 2025Article
- Translesion-synthesis-mediated bypass of DNA lesions occurs predominantly behind replication forks restarted by PrimPol.Cell reports · 2025Article
- The other side of the coin: protein deubiquitination by Ubiquitin-Specific Protease 1 in cancer progression and therapy.Future medicinal chemistry · 2025Review
- CRISPR knockout genome-wide screens identify the HELQ-RAD52 axis in regulating the repair of cisplatin-induced single-stranded DNA gaps.Nucleic acids research · 2024Article
- CAF-1 promotes efficient PrimPol recruitment to nascent DNA for single-stranded DNA gap formation.Nucleic acids research · 2024Article
- ATAD5-BAZ1B interaction modulates PCNA ubiquitination during DNA repair.Nature communications · 2024Article
- Positioning loss of PARP1 activity as the central toxic event in BRCA-deficient cancer.DNA repair · 2024Review
- SNF2L suppresses nascent DNA gap formation to promote DNA synthesis.Nucleic acids research · 2024Article
- Single-Stranded DNA Gap Accumulation Is a Functional Biomarker for USP1 Inhibitor Sensitivity.Cancer research · 2024Article
- PARP10 promotes the repair of nascent strand DNA gaps through RAD18 mediated translesion synthesis.Nature communications · 2024Article
- A perspective on tumor radiation resistance following high-LET radiation treatment.Journal of cancer research and clinical oncology · 2024Review
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
DNA replication stress-induced fork arrest represents a significant threat to genomic integrity. One major mechanism of replication restart involves repriming downstream of the arrested fork by PRIMPOL, leaving behind a single-stranded DNA (ssDNA) gap. Accumulation of nascent strand ssDNA gaps has emerged as a possible determinant of the cellular hypersensitivity to genotoxic agents in certain genetic backgrounds such as BRCA deficiency, but how gaps are converted into cytotoxic structures is still unclear. Here, we investigate the processing of PRIMPOL-dependent ssDNA gaps upon replication stress induced by hydroxyurea and cisplatin. We show that gaps generated in PRIMPOL-overexpressing cells are expanded in the 3'-5' direction by the MRE11 exonuclease, and in the 5'-3' direction by the EXO1 exonuclease. This bidirectional exonucleolytic gap expansion ultimately promotes their conversion into DSBs. We moreover identify the de-ubiquitinating enzyme USP1 as a critical regulator of PRIMPOL-generated ssDNA gaps. USP1 promotes gap accumulation during S-phase, and their expansion by the MRE11 and EXO1 nucleases. This activity of USP1 is linked to its role in de-ubiquitinating PCNA, suggesting that PCNA ubiquitination prevents gap accumulation during replication. Finally, we show that USP1 depletion suppresses DSB formation in PRIMPOL-overexpressing cells, highlighting an unexpected role for USP1 in promoting genomic instability under these conditions.
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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.