TDP2, TOP2, and SUMO: what is ZATT about?

Zagnoli-Vieira, Guido; Caldecott, Keith W.

doi:10.1038/cr.2017.147

Cited by 19 publications

(14 citation statements)

References 12 publications

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“…However, DSB repair was completed in patient cells within 8–24 hours, consistent with the established existence of alternative, nuclease-dependent mechanisms for repair of TOP2-induced DSBs in human cells. 4 , 13 , 14 Similar results were observed in human A549 cells in which TDP2 was mutated by CRISPR/Cas9 gene editing, confirming the importance of TDP2 for repair of TOP2-induced DSBs ( figure 3B ). More importantly, complementation of 850-BR cells with expression construct encoding recombinant human TDP2 restored normal rates of nuclear DSB repair, confirming that the DNA repair defect in the patient fibroblasts was the result of the TDP2 mutation ( figure 3C ).…”

Section: Resultssupporting

confidence: 77%

Confirming TDP2 mutation in spinocerebellar ataxia autosomal recessive 23 (SCAR23)

et al. 2018

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ObjectiveTo address the relationship between mutations in the DNA strand break repair protein tyrosyl DNA phosphodiesterase 2 (TDP2) and spinocerebellar ataxia autosomal recessive 23 (SCAR23) and to characterize the cellular phenotype of primary fibroblasts from this disease.MethodsWe have used exome sequencing, Sanger sequencing, gene editing and cell biology, biochemistry, and subcellular mitochondrial analyses for this study.ResultsWe have identified a patient in the United States with SCAR23 harboring the same homozygous TDP2 mutation as previously reported in 3 Irish siblings (c.425+1G>A). The current and Irish patients share the same disease haplotype, but the current patient lacks a homozygous variant present in the Irish siblings in the closely linked gene ZNF193, eliminating this as a contributor to the disease. The current patient also displays symptoms consistent with mitochondrial dysfunction, although levels of mitochondrial function in patient primary skin fibroblasts are normal. However, we demonstrate an inability in patient primary fibroblasts to rapidly repair topoisomerase-induced DNA double-strand breaks (DSBs) in the nucleus and profound hypersensitivity to this type of DNA damage.ConclusionsThese data confirm the TDP2 mutation as causative for SCAR23 and highlight the link between defects in nuclear DNA DSB repair, developmental delay, epilepsy, and ataxia.

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Section: Resultssupporting

confidence: 77%

Confirming TDP2 mutation in spinocerebellar ataxia autosomal recessive 23 (SCAR23)

et al. 2018

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“…In addition to this function, ZNT451/ZATT is able to recruit and activate TDP2. Due to the conformational change of TOP2, TDP2 is subsequently capable to gain access to the crosslink without preceding proteolysis [98,99]. After successful hydrolysis of the crosslink, the resulting DSB can be repaired directly by non homologous end joining [100].…”

Section: Enzymatic Hydrolysis Of a Dpcmentioning

confidence: 99%

Repair of DNA-protein crosslinks in plants

2020

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DNA-protein crosslinks represent a severe kind of DNA damage as they disturb essential processes, such as transcription and DNA replication, due to their bulkiness. To ensure the maintenance of genome integrity, it is necessary for all living organisms to repair these lesions in a timely manner. Over recent years, much knowledge has been obtained regarding the repair of DNA-protein crosslinks (DPC), but it was only recently that the first insights into the mechanisms of DPC repair in plants were obtained. The plant DPC repair network consists of at least three parallel pathways that resolve DPC by distinct biochemical mechanisms. The endonuclease MUS81 resolves the DPC by cleaving the DNA part of the crosslink, the protease WSS1A is able to degrade the protein part and the tyrosyl-DNA-phosphodiesterase TDP1 can hydrolyse the crosslink between a protein and the DNA. However, due to the variety of different DPC types and the evolutionary conservation of pathways between eukaryotes, we expect that future research will reveal additional factors involved in DPC repair in plants.

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“…Abortive TOP2ccs require removal by cellular DNA repair pathways. This involves, at least in part, hydrolytic removal of TOP2 peptide from the DNA break by tyrosyl-DNA phosphodiesterase 2 (TDP2) (Cortes Ledesma et al, 2009;Zagnoli-Vieira and Caldecott, 2017), thereby generating DSBs with 4-base cohesive overhangs that contain ligatable 5 0 -phosphate and 3 0 -hydroxyl termini (Zeng et al, 2011). Since they require no further processing, these protein-free ends are direct substrates for accurate non-homologous end joining (NHEJ) (Gó mez-Herreros et al, 2013).…”

Section: Introductionmentioning

confidence: 99%