DNA single‐strand break repair is impaired in aprataxin‐related ataxia

Hirano, Minoru; Yamamoto, Aya; Mori, Toshio; Lan, Li; Iwamoto, Takaaki; Akiyama, Masashi; Shimada, Kaoru; Furiya, Yoshiko; Kariya, Shingo; Asai, Hirohide; Yasui, Akira; Nishiwaki, Tomohisa; Imoto, Kyoko; Kobayashi, Nobuhiko; Kiriyama, Takao; Nagata, Tetsuya; Konishi, Noboru; Itoyama, Yasuto; Ueno, S.

doi:10.1002/ana.21078

Cited by 65 publications

(46 citation statements)

References 38 publications

(72 reference statements)

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“…A clear defect in cellular SSB repair, however, has only been reported for mutations in TDP1, as the attempts to demonstrate a similar defect in AOA1 failed to give consistent results. While aprataxin knock down appears to delay resealing of SSBs accumulated under conditions of GSH depletion (Hirano et al, 2007), other studies failed to detect slower repair kinetics of lesions caused by H 2 O 2 in AOA1 cells carrying different APTX mutations (Gueven et al, 2004) or in APTX knock out chicken DT40 cells, APTX -/-mouse fibroblasts, AOA1 human fibroblasts and AOA1 lymphoblast cell lines (Reynolds et al, 2009a). It was thus hypothesized that lack of consistent defects in SSB repair in aprataxin-defective cells, may reflect either the low abundance of 5'-AMP breaks or the availability of other factors for repair of these types of lesions (El-Khamisy et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…SSBR is known to be impaired in aprataxin knocked-down cells (Hirano et al, 2007) and a defect in cellular SSBR has also been reported in some AOA1 patient's derived cells (Mosesso et al, 2005;Gueven et al, 2007). Aprataxin is indeed recruited at sites of SSBs in an XRCC1-dependent manner and the targeting is mediated by PARP-1, a protein interacting with both XRCC1 and aprataxin and working as key player in SSBs detection (Harris et al, 2009).…”

Section: Introductionmentioning

confidence: 98%

“…The forkhead-associated (FHA) region at the N-terminus of aprataxin interacts with DNA repair proteins like XRCC1 and XRCC4 among the others (Sano et al, 2004), forming multiprotein complexes of the SSB and DSBrepair machinery respectively (SSBR and DSBR) (Clements et al, 2004;Gueven et al, 2004;Hirano et al, 2007;Caldecott, 2008).…”

Section: Introductionmentioning

confidence: 99%

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A novel nonsense mutation in the APTX gene associated with delayed DNA single‐strand break removal fails to enhance sensitivity to different genotoxic agents

et al. 2011

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APTX is the gene involved in ataxia with oculomotor apraxia type 1 (AOA1), a recessive disorder with early-onset cerebellar ataxia, oculomotor apraxia and peripheral neuropathy. The encoded protein, aprataxin, is a DNA repair protein processing the products of abortive ligations, 5'-adenylated DNA. We describe a novel nonsense mutation in APTX, c.892C>T (p.Gln298X), segregating in two AOA1 patients and leading to the loss of aprataxin protein in patient's cells. These cells, while exhibiting reduced catalase activity, are not hypersensitive to toxicity elicited by H 2 O 2 exposure at either physiologic or ice-bath temperature. On the other hand, the rate of repair of DNA single-strand-breaks (SSBs) induced in both conditions is always significantly slower in AOA1 cells. By using the alkylating agent methyl methane sulphonate (MMS) we confirmed the association of the APTX mutation with a DNA repair defect in the absence of detectable changes in susceptibility to toxicity. These results, while consistent with a role of aprataxin in the repair of SSBs induced by H 2 O 2 , or MMS, demonstrate that other mechanisms may be recruited in AOA1 cells to complete the repair process, although at a slower rate. Lack of hypersensitivity to the oxidant, or MMS, also implies that delayed repair is not per se a lethal event.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

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A novel nonsense mutation in the APTX gene associated with delayed DNA single‐strand break removal fails to enhance sensitivity to different genotoxic agents

et al. 2011

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“…Of all the known FHA domains, the FHA domain of PNK shares the highest sequence similarity with aprataxin, a product of the APTX gene mutated in the neurological disorder ataxia-oculomotor apraxia, that is involved in SSB repair [57][58][59][60][61]. In PNK the FHA domain serves a targeting role, directing PNK to the site of DNA damage by binding to phosphorylated XRCC1 and XRCC4, key components of the BER and NHEJ pathways, respectively.…”

Section: The Fha Domainmentioning

confidence: 99%

Polynucleotide Kinase as a Potential Target for Enhancing Cytotoxicity by Ionizing Radiation and Topoisomerase I Inhibitors

Bernstein¹,

Karimi‐Busheri²,

Rasouli-Nia³

et al. 2008

ACAMC

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The cytotoxicity of many antineoplastic agents is due to their capacity to damage DNA and there is evidence indicating that DNA repair contributes to the cellular resistance to such agents. DNA strand breaks constitute a significant proportion of the lesions generated by a broad range of genotoxic agents, either directly, or during the course of DNA repair. Strand breaks that are caused by many agents including ionizing radiation, topoisomerase I inhibitors, and DNA repair glycosylases such as NEIL1 and NEIL2, often contain 5'-hydroxyl and/or 3'-phosphate termini. These ends must be converted to 5'-phosphate and 3'-hydroxyl termini in order to allow DNA polymerases and ligases to catalyze repair synthesis and strand rejoining. A key enzyme involved in this end-processing is polynucleotide kinase (PNK), which possesses two enzyme activities, a DNA 5'-kinase activity and a 3'-phosphatase activity. PNK participates in the single-strand break repair pathway and the nonhomologous end joining pathway for double-strand break repair. RNAi-mediated down-regulation of PNK renders cells more sensitive to ionizing radiation and camptothecin, a topoisomerase I inhibitor. Structural analysis of PNK revealed the protein is composed of three domains, the kinase domain at the C-terminus, the phosphatase domain in the centre and a forkhead associated (FHA) domain at the N-terminus. The FHA domain plays a critical role in the binding of PNK to other DNA repair proteins. Thus each PNK domain may be a suitable target for small molecule inhibition to effectively reduce resistance to ionizing radiation and topoisomerase I inhibitors. KeywordsDNA damage; DNA repair; small molecule inhibitors; polynucleotide kinase; FHA; kinase; phosphatase Cancer therapy and DNA damage and repairCancer continues to be a major health problem. This year (2007) it is estimated that approximately 1.6 million individuals will be diagnosed with cancer in the USA and Canada (excluding basal and squamous cell skin cancer) and that approximately 630,000 will die from cancer (American Cancer Society and Canadian Cancer Society). Despite major advances in targeted chemotherapy, the major forms of therapy continue to be surgery, radiotherapy and conventional chemotherapy. The cellular target for radiotherapy and many conventional drugs Corresponding authors: Michael Weinfeld, Experimental Oncology, Cross Cancer Institute, 11560 University Ave, Edmonton, Alberta T6G 1Z2, Canada, michaelw@cancerboard.ab.ca, Tel: (780) 432 8438, Mark Glover, Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada, mark.glover@ualberta.ca, Tel: (780) 492-2136. NIH Public Access Author ManuscriptAnticancer Agents Med Chem. Author manuscript; available in PMC 2010 October 22. Published in final edited form as:Anticancer Agents Med Chem. 2008 May ; 8(4): 358-367. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscriptis the DNA within the nuclei (and possibly mitochondria). Consequently, the levels of induced DNA damage and t...

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“…One of the most robust set of data that demonstrates association between DNA repair and neurodegenerative diseases comes from studies on early onset ataxia with ocular motor apraxia and hypoalbuminemia/ataxia with oculomotor apraxia type 1 (EAOH/AOA1), an autosomal recessive form of cerebellar ataxia caused by mutations in the aprataxin (APTX) gene. It was shown that aprataxin participates in DNA repair suggesting that genes involved in DNA repair pathways might have a role in neurodegeneration (Hirano et al, 2007;Takahashi et al, 2007). Also parkin, encoded by one of the causative genes of Parkinson's disease (PD), seems to contribute to DNA repair (Kao, 2009).…”

Section: Introductionmentioning

confidence: 99%

Variants and Polymorphisms of DNA Repair Genes and Neurodegenerative Diseases

Coppedè¹

2011

DNA Repair

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DNA single‐strand break repair is impaired in aprataxin‐related ataxia

Abstract: This study provides the first direct evidence for the functional involvement of APTX in SSBR and in vivo DNA damage in EAOH/AOA1, and suggests a benefit of antioxidant treatment.

Cited by 65 publications

References 38 publications

A novel nonsense mutation in the APTX gene associated with delayed DNA single‐strand break removal fails to enhance sensitivity to different genotoxic agents

A novel nonsense mutation in the APTX gene associated with delayed DNA single‐strand break removal fails to enhance sensitivity to different genotoxic agents

Polynucleotide Kinase as a Potential Target for Enhancing Cytotoxicity by Ionizing Radiation and Topoisomerase I Inhibitors

Variants and Polymorphisms of DNA Repair Genes and Neurodegenerative Diseases

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