ArticlePLoS genetics2013
TDP2-dependent non-homologous end-joining protects against topoisomerase II-induced DNA breaks and genome instability in cells and in vivo.
Article in PLoS genetics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 105 papers.
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105 citing papers in PubMed, 162 citations in OpenAlex.
- Trial
- End processing in NHEJ by Polymerase λ and PNKP is coordinated during short-range synapsis.Nature communications · 2026Article
- MRE11 suppresses germline mutagenesis at meiotic double-strand breaks in mice.Genes & development · 2026Article
- Article
- The SMARCA4 subunit of the SWI/SNF complex prevents genome instability at G quadruplexes.Genome biology · 2026Article
- MRE11 suppresses germline mutagenesis at meiotic double-strand breaks in mice.bioRxiv : the preprint server for biology · 2026Article
- H263A and SCAN1/H493R mutant TDP1 block TOP1-induced double-strand break repair during gene transcription in quiescent cells and promote cell death.Cell death & disease · 2025Article
- ARID1A stabilizes non-homologous end joining factors at DNA breaks induced by the G4 ligand pyridostatin.Cell reports · 2025Article
- Mechanisms and regulation of DNA end resection in the maintenance of genome stability.Nature reviews. Molecular cell biology · 2025Review
- Topoisomerase II Inhibition in Cancer: A Focus on Metal Complexes.Mini reviews in medicinal chemistry · 2025Review
- From the TOP: Formation, recognition and resolution of topoisomerase DNA protein crosslinks.DNA repair · 2024Review
- A novel pathogenic variant in TDP2 causes spinocerebellar ataxia autosomal recessive 23 accompanied by pituitary tumor and hyperhidrosis: a case report.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2024Article
- TDP2 is a regulator of estrogen-responsive oncogene expression.NAR cancer · 2024Article
- Enzymatic Processing of DNA-Protein Crosslinks.Genes · 2024Review
- Tyrosyl-DNA phosphodiesterase 2 (Tdp2) repairs DNA-protein crosslinks and protects against double strand breaksFrontiers in cell and developmental biology · 2024Article
- RAD54L2 counters TOP2-DNA adducts to promote genome stability.Science advances · 2023Article
- Article
- Inactivating TDP2 missense mutation in siblings with congenital abnormalities reminiscent of fanconi anemia.Human genetics · 2023Article
- DNA-PK inhibition extends the therapeutic effects of Top2 poisoning to non-proliferating cells, increasing activity at a cost.Scientific reports · 2023Article
- Two distinct long-range synaptic complexes promote different aspects of end processing prior to repair of DNA breaks by non-homologous end joining.Molecular cell · 2023Article
45 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 4 institutions in 3 countries.
Funding
Abstract
Anticancer topoisomerase "poisons" exploit the break-and-rejoining mechanism of topoisomerase II (TOP2) to generate TOP2-linked DNA double-strand breaks (DSBs). This characteristic underlies the clinical efficacy of TOP2 poisons, but is also implicated in chromosomal translocations and genome instability associated with secondary, treatment-related, haematological malignancy. Despite this relevance for cancer therapy, the mechanistic aspects governing repair of TOP2-induced DSBs and the physiological consequences that absent or aberrant repair can have are still poorly understood. To address these deficits, we employed cells and mice lacking tyrosyl DNA phosphodiesterase 2 (TDP2), an enzyme that hydrolyses 5'-phosphotyrosyl bonds at TOP2-associated DSBs, and studied their response to TOP2 poisons. Our results demonstrate that TDP2 functions in non-homologous end-joining (NHEJ) and liberates DSB termini that are competent for ligation. Moreover, we show that the absence of TDP2 in cells impairs not only the capacity to repair TOP2-induced DSBs but also the accuracy of the process, thus compromising genome integrity. Most importantly, we find this TDP2-dependent NHEJ mechanism to be physiologically relevant, as Tdp2-deleted mice are sensitive to TOP2-induced damage, displaying marked lymphoid toxicity, severe intestinal damage, and increased genome instability in the bone marrow. Collectively, our data reveal TDP2-mediated error-free NHEJ as an efficient and accurate mechanism to repair TOP2-induced DSBs. Given the widespread use of TOP2 poisons in cancer chemotherapy, this raises the possibility of TDP2 being an important etiological factor in the response of tumours to this type of agent and in the development of treatment-related malignancy.
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