ArticleThe Journal of biological chemistry2009
Implication of checkpoint kinase-dependent up-regulation of ribonucleotide reductase R2 in DNA damage response.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 87 papers, 1 of them a synthesis that pooled it.
What it found
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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.
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Who cites it
87 citing papers in PubMed, 1 synthesis or guideline pooled it, 147 citations in OpenAlex.
- Prognostic and therapeutic significance of ribonucleotide reductase small subunit M2 in estrogen-negative breast cancers.BMC cancer · 2014Pooled it
- Phase II trial of the ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehydethiosemicarbazone plus gemcitabine in patients with advanced biliary tract cancer.Cancer chemotherapy and pharmacology · 2011Trial
- An updated view on lagging strand DNA replication: implications for the replication stress response.Cell cycle (Georgetown, Tex.) · 2026Article
- Roles of RRM2 and RRM2B in pyrimidine stress responses and differentiation of acute myeloid leukemia cells.Cell death discovery · 2026Article
- CHK1 as a Metabolic and Immunological Regulator: Implications for Cancer Therapy.Oncology research · 2026Review
- Shining light on drug discovery: optogenetic screening for TopBP1 biomolecular condensate inhibitors.NAR cancer · 2025Article
- Identification of a Proteolysis-Targeting-Chimera that Addresses Activated Checkpoint Kinase-1 Reveals its Non-Catalytic Functions in Tumor Cells.Angewandte Chemie (International ed. in English) · 2025Article
- TopBP1 biomolecular condensates as a new therapeutic target in advanced-stage colorectal cancer.eLife · 2025Article
- A high-resolution, nanopore-based artificial intelligence assay for DNA replication stress in human cancer cells.Nature communications · 2025Article
- Bioinformatics Analysis Screening and Identification of Key Biomarkers and Drug Targets in Human Glioblastoma.Current medicinal chemistry · 2025Article
- DNA damage repair-related methylated genes RRM2 and GAPDH are prognostic biomarkers associated with immunotherapy for lung adenocarcinoma.Genetics and molecular biology · 2025Article
- Membrane RRM2-positive cells represent a malignant population with cancer stem cell features in intrahepatic cholangiocarcinoma.Journal of experimental & clinical cancer research : CR · 2024Article
- The thioredoxin system determines CHK1 inhibitor sensitivity via redox-mediated regulation of ribonucleotide reductase activity.Nature communications · 2024Article
- Wounding increases nuclear ploidy in wound-proximal epidermal cells of themicroPublication biology · 2024Article
- Antibody dependent cell-mediated cytotoxicity selection pressure induces diverse mechanisms of resistance.Cancer biology & therapy · 2023Article
- RRM2‑mediated Wnt/β‑catenin signaling pathway activation in lung adenocarcinoma: A potential prognostic biomarker.Oncology letters · 2023Article
- SARS-CoV-2 infection induces DNA damage, through CHK1 degradation and impaired 53BP1 recruitment, and cellular senescence.Nature cell biology · 2023Article
- Cell cycle regulation of the psoriasis associated gene CCHCR1 by transcription factor E2F1.PloS one · 2023Article
- Article
- HNRNPK alleviates RNA toxicity by counteracting DNA damage in C9orf72 ALS.Acta neuropathologica · 2022Article
27 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
Abstract
To investigate drug mechanisms of action and identify molecular targets for the development of rational drug combinations, we conducted synthetic small interfering RNA (siRNA)-based RNAi screens to identify genes whose silencing affects anti-cancer drug responses. Silencing of RRM1 and RRM2, which encode the large and small subunits of the human ribonucleotide reductase complex, respectively, markedly enhanced the cytotoxicity of the topoisomerase I inhibitor camptothecin (CPT). Silencing of RRM2 was also found to enhance DNA damage as measured by histone gamma-H2AX. Further studies showed that CPT up-regulates both RRM1 and RRM2 mRNA and protein levels and induces the nuclear translocation of RRM2. The checkpoint kinase 1 (Chk1) was up-regulated and activated in response to CPT, and CHEK1 down-regulation by siRNA and small molecule inhibitors of Chk1 blocked RRM2 induction by CPT. CHEK1 siRNA also suppressed E2F1 up-regulation by CPT, and silencing of E2F1 suppressed the up-regulation of RRM2. Silencing of ATR or ATM and inhibition of ATM activity by KU-55933 blocked Chk1 activation and RRM2 up-regulation. This study links the known components of CPT-induced DNA damage response with proteins required for the synthesis of dNTPs and DNA repair. Specifically, we propose that upon DNA damage, Chk1 activation, mediated by ATM and ATR, up-regulates RRM2 expression through the E2F1 transcription factor. Up-regulation in RRM2 expression levels coupled with its nuclear recruitment suggests an active role for ribonucleotide reductase in the cellular response to CPT-mediated DNA damage that could potentially be exploited as a strategy for enhancing the efficacy of topoisomerase I inhibitors.
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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.