Hereditary ataxia SCAN1 cells are defective for the repair of transcription-dependent topoisomerase I cleavage complexes

Miao, Ze‐Hong; Agama, Keli; Sordet, Olivier; Povirk, Lawrence F.; Kohn, Kurt W.; Pommier, ﻿Yves

doi:10.1016/j.dnarep.2006.07.004

Cited by 87 publications

(97 citation statements)

References 26 publications

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“…Specifically, homozygous mutant SCAN1 cells have been shown to accumulate more total DNA strand breaks than normal lymphoblastoid cells after treatment with CPT [24,72]. SCAN1 cells have also demonstrated enhanced sensitivity to the killing effects of CPT [28,72]. Furthermore, complementary studies have shown that overexpression of wild-type Tdp1 protects cells against CPT-induced cell death [26,73], whereas the inactive mutant Tdp1 H263A does not [26].…”

Section: Rationale For Targeting Tdp1 For Cancer Therapymentioning

confidence: 83%

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Tyrosyl-DNA Phosphodiesterase as a Target for Anticancer Therapy

Dexheimer¹,

Antony²,

Marchand³

et al. 2008

ACAMC

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144

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Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a recently discovered enzyme that catalyzes the hydrolysis of 3′-phosphotyrosyl bonds. Such linkages form in vivo following the DNA processing activity of topoisomerase I (Top1). For this reason, Tdp1 has been implicated in the repair of irreversible Top1-DNA covalent complexes, which can be generated by either exogenous or endogenous factors. Tdp1 has been regarded as a potential therapeutic co-target of Top1 in that it seemingly counteracts the effects of Top1 inhibitors, such as camptothecin and its clinically used derivatives. Thus, by reducing the repair of Top1-DNA lesions, Tdp1 inhibitors have the potential to augment the anticancer activity of Top1 inhibitors provided there is a presence of genetic abnormalities related to DNA checkpoint and repair pathways. Human Tdp1 can also hydrolyze other 3′-end DNA alterations including 3′-phosphoglycolates and 3′-abasic sites indicating it may function as a general 3′-DNA phosphodiesterase and repair enzyme. The importance of Tdp1 in humans is highlighted by the observation that a recessive mutation in the human TDP1 gene is responsible for the inherited disorder, spinocerebellar ataxia with axonal neuropathy (SCAN1). This review provides a summary of the biochemical and cellular processes performed by Tdp1 as well as the rationale behind the development of Tdp1 inhibitors for anticancer therapy.

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Section: Rationale For Targeting Tdp1 For Cancer Therapymentioning

confidence: 83%

Section: Rationale For Targeting Tdp1 For Cancer Therapymentioning

confidence: 99%

Tyrosyl-DNA Phosphodiesterase as a Target for Anticancer Therapy

Dexheimer¹,

Antony²,

Marchand³

et al. 2008

ACAMC

Self Cite

144

203

View full text Add to dashboard Cite

show abstract

“…TDP1 was originally discovered in yeast (34) and has been implicated in the repair of stalled Top1-DNA covalent complexes (38,39). The ability of TDP1 to resolve 3′-phosphotyrosyl linkages is consistent with its role in protecting cells against Top1-DNA lesions (40)(41)(42)(43).…”

mentioning

confidence: 74%

“…Homozygous mutation of TDP1 causes spinocerebellar ataxia with axonal neuropathy (SCAN1), an autosomal recessive neurodegenerative syndrome (44). Cells from SCAN1 patients are hypersensitive to the specific Top1 poison camptothecin and accumulate elevated Top1-associated DNA breaks in response to camptothecin (39,43,45).…”

mentioning

confidence: 99%

Role of tyrosyl-DNA phosphodiesterase (TDP1) in mitochondria

Das

Dexheimer

Maddali

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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152

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Human tyrosyl-DNA phosphodiesterase (TDP1) hydrolyzes the phosphodiester bond at a DNA 3′-end linked to a tyrosyl moiety and has been implicated in the repair of topoisomerase I (Top1)-DNA covalent complexes. TDP1 can also hydrolyze other 3′-end DNA alterations including 3′-phosphoglycolate and 3′-abasic sites, and exhibits 3′-nucleosidase activity indicating it may function as a general 3′-end-processing DNA repair enzyme. Here, using laser confocal microscopy, subcellular fractionation and biochemical analyses we demonstrate that a fraction of the TDP1 encoded by the nuclear TDP1 gene localizes to mitochondria. We also show that mitochondrial base excision repair depends on TDP1 activity and provide evidence that TDP1 is required for efficient repair of oxidative damage in mitochondrial DNA. Together, our findings provide evidence for TDP1 as a novel mitochondrial enzyme.DNA repair | ligase III | oxidative DNA damage | topoisomerase I | mitochondrial BER

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“…SCAN1 is caused by a missense mutation in the Tdp1 catalytic site. As in yeast, the human Tdp1 protein plays a role in the repair of topoisomerase I-DNA complex lesions in SCAN1 cells (El-Khamisy et al, 2005;Miao et al, 2006). SCAN1 cells are hypersensitive to CPT (Interthal et al, 2005;Miao et al, 2006) and accumulate single-strand break and double-strand break DNAs by CPT (El-Khamisy et al, 2005).…”

mentioning

confidence: 99%

Identification of Tyrosyl-DNA Phosphodiesterase as a Novel DNA Damage Repair Enzyme in Arabidopsis

et al. 2010

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Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a key enzyme that hydrolyzes the phosphodiester bond between tyrosine of topoisomerase and 3#-phosphate of DNA and repairs topoisomerase-mediated DNA damage during chromosome metabolism. However, functional Tdp1 has only been described in yeast and human to date. In human, mutations of the Tdp1 gene are involved in the disease spinocerebellar ataxia with axonal neuropathy. In plants, we have identified the functional nuclear protein AtTDP, homolog to human Tdp1 from Arabidopsis (Arabidopsis thaliana). The recombinant AtTDP protein certainly hydrolyzes the 3#-phosphotyrosyl DNA substrates related to repairing in vivo topoisomerase I-DNA-induced damage. The loss-of-function AtTDP mutation displays developmental defects and dwarf phenotype in Arabidopsis. This phenotype is substantially caused by decreased cell numbers without any change of individual cell sizes. The tdp plants exhibit hypersensitivities to camptothecin, a potent topoisomerase I inhibitor, and show rigorous cell death in cotyledons and rosette leaves, suggesting the failure of DNA damage repair in tdp mutants. These results indicate that AtTDP plays a clear role in the repair of topoisomerase I-DNA complexes in Arabidopsis.

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Hereditary ataxia SCAN1 cells are defective for the repair of transcription-dependent topoisomerase I cleavage complexes

Cited by 87 publications

References 26 publications

Tyrosyl-DNA Phosphodiesterase as a Target for Anticancer Therapy

Tyrosyl-DNA Phosphodiesterase as a Target for Anticancer Therapy

Role of tyrosyl-DNA phosphodiesterase (TDP1) in mitochondria

Identification of Tyrosyl-DNA Phosphodiesterase as a Novel DNA Damage Repair Enzyme in Arabidopsis

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