Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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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PMID:TDP2-dependent non-homologous end-joining protects against topoisomerase II-induced DNA breaks and genome instability in cells and in vivo. 2350 91

Hematologic malignancies are often associated with chromosomal rearrangements that lead to the expression of chimeric fusion proteins. Rearrangements of the genes encoding two nucleoporins, NUP98 and NUP214, have been implicated in the pathogenesis of several types of hematologic malignancies, particularly acute myeloid leukemia. NUP98 rearrangements result in fusion of an N-terminal portion of NUP98 to one of numerous proteins. These rearrangements often follow treatment with topoisomerase II inhibitors and tend to occur in younger patients. They have been shown to induce leukemia in mice and to enhance proliferation and disrupt differentiation in primary human hematopoietic precursors. NUP214 has only a few fusion partners. DEK-NUP214 is the most common NUP214 fusion in AML; it tends to occur in younger patients and is usually associated with FLT3 internal tandem duplications. The leukemogenic activity of NUP214 fusions is less well characterized. Normal nucleoporins, including NUP98 and NUP214, have important functions in nucleocytoplasmic transport, transcription, and mitosis. These functions and their disruptions by oncogenic nucleoporin fusions are discussed.
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PMID:Nucleoporins and nucleocytoplasmic transport in hematologic malignancies. 2465 37


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