ArticleOncotarget2017
The dominant role of proofreading exonuclease activity of replicative polymerase ε in cellular tolerance to cytarabine (Ara-C).
Article in Oncotarget, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 49 citations in OpenAlex.
- Response of the replisome to araA and araC suggests a mechanism for arabinosyl nucleoside tolerance.The EMBO journal · 2026Article
- Targeting Genome Maintenance Defects of Cancers Using Chain-Terminating Nucleoside Analogs.Cancer science · 2026Review
- Generation of Human Haematopoietic Model Cell Lines Revealed Distinct Replication Stress Tolerance Between Two OncogenicBiomolecules · 2026Article
- REV7 associates with ATRIP and inhibits ATR kinase activity.Nucleic acids research · 2026Article
- Anti-orthopoxvirus drugs inhibit lumpy skin disease virus replication by targeting viral DNA polymerase.PLoS pathogens · 2026Article
- Incorporation and Repair of Epigenetic Intermediates as Potential Chemotherapy Agents.Molecules (Basel, Switzerland) · 2025Article
- The flap endonuclease-1 promotes cellular tolerance to a chain-terminating nucleoside analog, alovudine, by counteracting the toxic effect of 53BP1.Nucleic acids research · 2025Article
- Role of TDP2 in the repair of DNA damage induced by the radiomimetic drug Bleomycin.Genes and environment : the official journal of the Japanese Environmental Mutagen Society · 2025Article
- Comprehensive whole-genome sequencing reveals origins of mutational signatures associated with aging, mismatch repair deficiency and temozolomide chemotherapy.Nucleic acids research · 2025Article
- Molecular dependencies and genomic consequences of a global DNA damage tolerance defect.Genome biology · 2024Article
- RAD18- and BRCA1-dependent pathways promote cellular tolerance to the nucleoside analog ganciclovir.Genes to cells : devoted to molecular & cellular mechanisms · 2024Article
- REV3 promotes cellular tolerance to 5-fluorodeoxyuridine by activating translesion DNA synthesis and intra-S checkpoint.PLoS genetics · 2024Article
- REV7-p53 interaction inhibits ATM-mediated DNA damage signaling.Cell cycle (Georgetown, Tex.) · 2024Article
- Homologous recombination contributes to the repair of acetaldehyde-induced DNA damage.Cell cycle (Georgetown, Tex.) · 2024Article
- The proofreading exonuclease of leading-strand DNA polymerase epsilon prevents replication fork collapse at broken template strands.Nucleic acids research · 2023Article
- Article
- The Advances of Broad-Spectrum and Hot Anti-Coronavirus Drugs.Microorganisms · 2022Review
- XRCC1 counteracts poly(ADP ribose)polymerase (PARP) poisons, olaparib and talazoparib, and a clinical alkylating agent, temozolomide, by promoting the removal of trapped PARP1 from broken DNA.Genes to cells : devoted to molecular & cellular mechanisms · 2022Article
- Mechanisms of Coronavirus Genome Stability As Potential Targets for Antiviral Drugs.Herald of the Russian Academy of Sciences · 2022Article
- Enhanced cytarabine-induced killing in OGG1-deficient acute myeloid leukemia cells.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
Corrections and comments
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Authors and funding
16 authors at 6 institutions in 3 countries.
Funding
Abstract
Chemotherapeutic nucleoside analogs, such as Ara-C, 5-Fluorouracil (5-FU) and Trifluridine (FTD), are frequently incorporated into DNA by the replicative DNA polymerases. However, it remains unclear how this incorporation kills cycling cells. There are two possibilities: Nucleoside analog triphosphates inhibit the replicative DNA polymerases, and/or nucleotide analogs mis-incorporated into genomic DNA interfere with the next round of DNA synthesis as replicative DNA polymerases recognize them as template DNA lesions, arresting synthesis. To address the first possibility, we selectively disrupted the proofreading exonuclease activity of DNA polymerase ε (Polε), the leading-strand replicative polymerase in avian DT40 and human TK6 cell lines. To address the second, we disrupted RAD18, a gene involved in translesion DNA synthesis, a mechanism that relieves stalled replication. Strikingly, POLE1exo-/- cells, but not RAD18-/- cells, were hypersensitive to Ara-C, while RAD18-/- cells were hypersensitive to FTD. gH2AX focus formation following a pulse of Ara-C was immediate and did not progress into the next round of replication, while gH2AX focus formation following a pulse of 5-FU and FTD was delayed to the next round of replication. Biochemical studies indicate that human proofreading-deficient Polε-exo- holoenzyme incorporates Ara-CTP, but subsequently extend from this base several times less efficiently than from intact nucleotides. Together our results suggest that Ara-C acts by blocking extension of the nascent DNA strand and is counteracted by the proofreading activity of Polε, while 5-FU and FTD are efficiently incorporated but act as replication fork blocks in the subsequent S phase, which is counteracted by translesion synthesis.
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Registered trials
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.