ArticleCancer research2008
ATM and the Mre11-Rad50-Nbs1 complex respond to nucleoside analogue-induced stalled replication forks and contribute to drug resistance.
Article in Cancer research, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT07493668 (A Phase 2, Multicenter, Randomized, Open-label Study Comparing Fostrox + Lenvatinib vs. Lenvatinib in Patients With Locally Advanced or Unresectable Advanced Hepatocellular Carcinoma), which is not on this map. Cited by 23 papers.
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.
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.
A Phase 2, Multicenter, Randomized, Open-label Study Comparing Fostrox + Lenvatinib vs. Lenvatinib in Patients With Locally Advanced or Unresectable Advanced Hepatocellular Carcinoma (HCC) Who Have Received First-line Combination Immunotherapy
Who cites it
23 citing papers in PubMed, 52 citations in OpenAlex.
- A Phase 1a/1b Study of Fostroxacitabine Bralpamide (Fostrox) Monotherapy in Hepatocellular Carcinoma and Solid Tumor Liver Metastases.Journal of hepatocellular carcinoma · 2024Trial
- Pancreatic cancer organoids derived from EUS-guided fine needle aspiration specimens can be used to predict chemotherapy resistance.Scientific reports · 2025Article
- A ferrocene-containing nucleoside analogue targets DNA replication in pancreatic cancer cells.Metallomics : integrated biometal science · 2022Article
- Acquired temozolomide resistance in MGMTCell death & disease · 2022Article
- MYBL2 and ATM suppress replication stress in pluripotent stem cells.EMBO reports · 2021Article
- Mre11 exonuclease activity removes the chain-terminating nucleoside analog gemcitabine from the nascent strand during DNA replication.Science advances · 2020Article
- Article
- Perturbing cohesin dynamics drives MRE11 nuclease-dependent replication fork slowing.Nucleic acids research · 2019Article
- Superresolution imaging of individual replication forks reveals unexpected prodrug resistance mechanism.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- MRE11 and EXO1 nucleases degrade reversed forks and elicit MUS81-dependent fork rescue in BRCA2-deficient cells.Nature communications · 2017Article
- Article
- Plk1 Inhibitors in Cancer Therapy: From Laboratory to Clinics.Molecular cancer therapeutics · 2016Review
- Plk1 inhibition enhances the efficacy of gemcitabine in human pancreatic cancer.Cell cycle (Georgetown, Tex.) · 2016Article
- Hyperthermia inhibits recombination repair of gemcitabine-stalled replication forks.Journal of the National Cancer Institute · 2014Article
- Gemcitabine induces poly (ADP-ribose) polymerase-1 (PARP-1) degradation through autophagy in pancreatic cancer.PloS one · 2014Article
- Ovarian cancer: in search of better marker systems based on DNA repair defects.International journal of molecular sciences · 2013Review
- Phase I and pharmacologic trial of cytosine arabinoside with the selective checkpoint 1 inhibitor Sch 900776 in refractory acute leukemias.Clinical cancer research : an official journal of the American Association for Cancer Research · 2012Article
- P38MAPK is a major determinant of the balance between apoptosis and autophagy triggered by 5-fluorouracil: implication in resistance.Oncogene · 2012Article
- The human immunodeficiency virus protease inhibitor ritonavir inhibits lung cancer cells, in part, by inhibition of survivin.Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer · 2011Article
- Requirement for NBS1 in the S phase checkpoint response to DNA methylation combined with PARP inhibition.DNA repair · 2011Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
The Mre11-Rad50-Nbs1 complex and autophosphorylated Ser(1981)-ATM are involved in recognizing and repairing DNA damage, such as double-strand breaks (DSB). However, the role of these factors in response to stalled replication forks is not clear. Nucleoside analogues are agents that are incorporated into DNA during replication, which cause stalling of replication forks. The molecular mechanisms that sense these events may signal for DNA repair and contribute to survival but are poorly understood. Cellular responses to both DSBs and stalled replication forks are marked by H2AX phosphorylation on Ser(139) (gamma-H2AX), which forms nuclear foci at sites of DNA damage. Here, concentrations of the nucleoside analogues 1-beta-d-arabinofuranosylcytosine (cytarabine; ara-C), gemcitabine, and troxacitabine, which inhibited DNA synthesis by 90% within 2 hours, were determined for each agent. Using gamma-H2AX as a marker for changes in chromatin structure, we show that Mre11, Rad50, Nbs1, and phosphorylated ATM respond to nucleoside analogue-induced stalled replication forks by forming nuclear foci that colocalize with gamma-H2AX within 2 hours. Because neither DSBs nor single-strand breaks were detectable after nucleoside analogue exposure, we conclude that this molecular response is not due to the presence of DNA breaks. Deficiencies in ATM, Mre11, or Rad50 led to a 2- to 5-fold increase in clonogenic sensitization to gemcitabine, whereas Nbs1 and H2AX deficiency did not affect reproductive growth. Taken together, these results suggest that ATM, Mre11, and Rad50 are required for survival after replication fork stalling, whereas Nbs1 and H2AX are inconsequential.
Indexed as
Identifiers
What OpenQuestion holds
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.