ArticleNucleic acids research2013
5-Aza-2'-deoxycytidine causes replication lesions that require Fanconi anemia-dependent homologous recombination for repair.
Article in Nucleic acids research, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 74 citations in OpenAlex.
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- DNA-protein cross-links emerge as major contributors to chemotherapeutic cytotoxicity at physiological equitoxic doses.Scientific reports · 2025Article
- Low dose DNA methyltransferase inhibitors potentiate PARP inhibitors in homologous recombination repair deficient tumors.Breast cancer research : BCR · 2025Article
- A multiomics approach reveals RNA dynamics promote cellular sensitivity to DNA hypomethylation.Scientific reports · 2024Article
- The type of DNA damage response after decitabine treatment depends on the level of DNMT activity.Life science alliance · 2024Article
- TOPORS E3 ligase mediates resistance to hypomethylating agent cytotoxicity in acute myeloid leukemia cells.Nature communications · 2024Article
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- Comprehensive comparison between azacytidine and decitabine treatment in an acute myeloid leukemia cell line.Clinical epigenetics · 2022Article
- Role of Cockayne Syndrome Group B Protein in Replication Stress: Implications for Cancer Therapy.International journal of molecular sciences · 2022Review
- Zebularine, a DNA Methylation Inhibitor, Activates Anthocyanin Accumulation in Grapevine Cells.Genes · 2022Article
- Promoter Gene Methylation Regulates Clooxygenase-2 Expression in Androgen-Dependent and Independent Prostate Cancer Cells.World journal of oncology · 2022Article
- Epigenetic Anti-Cancer Treatment With a Stabilized Carbocyclic Decitabine Analogue.Chemistry (Weinheim an der Bergstrasse, Germany) · 2022Article
- The Contrasting Delayed Effects of Transient Exposure of Colorectal Cancer Cells to Decitabine or Azacitidine.Cancers · 2022Article
- Deregulation of Transcriptional Enhancers in Cancer.Cancers · 2021Review
- 5-AZA-dC induces epigenetic changes associated with modified glycosylation of secreted glycoproteins and increased EMT and migration in chemo-sensitive cancer cells.Clinical epigenetics · 2021Article
- Article
- Treatment of human cells with 5-aza-dC induces formation of PARP1-DNA covalent adducts at genomic regions targeted by DNMT1.DNA repair · 2020Article
- Making it or breaking it: DNA methylation and genome integrity.Essays in biochemistry · 2020Review
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
5-Aza-2'-deoxycytidine (5-azadC) is a DNA methyltransferase (DNMT) inhibitor increasingly used in treatments of hematological diseases and works by being incorporated into DNA and trapping DNMT. It is unclear what DNA lesions are caused by 5-azadC and if such are substrates for DNA repair. Here, we identify that 5-azadC induces DNA damage as measured by γ-H2AX and 53BP1 foci. Furthermore, 5-azadC induces radial chromosomes and chromatid breaks that depend on active replication, which altogether suggest that trapped DNMT collapses oncoming replication forks into double-strand breaks. We demonstrate that RAD51-mediated homologous recombination (HR) is activated to repair 5-azadC collapsed replication forks. Fanconi anemia (FA) is a rare autosomal recessive disorder, and deaths are often associated with leukemia. Here, we show that FANCG-deficient cells fail to trigger HR-mediated repair of 5-azadC-induced lesions, leading to accumulation of chromatid breaks and inter-chromosomal radial fusions as well as hypersensitivity to the cytotoxic effects of 5-azadC. These data demonstrate that the FA pathway is important to protect from 5-azadC-induced toxicity. Altogether, our data demonstrate that cytotoxicity of the epigenetic drug 5-azadC can, at least in part, be explained by collapsed replication forks requiring FA-mediated HR for repair.
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