Journal
NUCLEIC ACIDS RESEARCH
Volume 41, Issue 11, Pages 5827-5836Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkt270
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Funding
- Spanish Ministry of Education and Science [BFU2007-61301]
- Junta de Andalucia, Spain [BIO-120]
- Swedish Cancer Society
- Swedish Children's Cancer Foundation
- Swedish Research Council
- Swedish Pain Relief Foundation
- Soderberg Foundation
- Plan Propio of University of Seville, Spain
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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 gamma-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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