Abstract
Spinocerebellar ataxia with axonal neuropathy (SCAN1) is an autosomal recessive disorder caused by a specific point mutation (c.1478A>G, p.H493R) in the tyrosyl-DNA phosphodiesterase (TDP1) gene. Functional and genetic studies suggest that this mutation, which disrupts the active site of the Tdp1 enzyme, causes disease by a combination of decreased catalytic activity and stabilization of the normally transient covalent Tdp1-DNA intermediate. This covalent reaction intermediate can form during the repair of stalled topoisomerase I-DNA adducts or oxidatively damaged bases at the 3′ end of the DNA at a strand break. However, our current understanding of the biology of Tdp1 function in humans is limited and does not allow us to fully elucidate the disease mec
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References
de Boer J, Hoeijmakers JH. Nucleotide excision repair and human syndromes. Carcinogenesis 2000; 21:453–60.
O’Driscoll M, Jeggo PA. The role of double-strand break repair—insights from human genetics. Nat Rev Genet 2006; 7:45–54.
Friedberg EC, Walker GC, Siede W et al. Disease states associated with defective biological responses to DNA damage. DNA Repair and Mutagenesis. Washington: ASM Press, 2006;863–1080.
Subba Rao K. Mechanisms of disease: DNA repair defects and neurological disease. Nat Clin Pract Neurol 2007; 3:162–72.
Barzilai A. The contribution of the DNA damage response to neuronal viability. Antioxid Redox Signal 2007; 9:211–8.
Chen L, Lee HM, Greeley GH Jr et al. Accumulation of oxidatively generated DNA damage in the brain: a mechanism of neurotoxicity. Free Radic Biol Med 2007; 42:385–93.
Lombard DB, Chua KF, Mostoslavsky R et al. DNA repair, genome stability and aging. Cell 2005; 120:497–512.
Gorbunova V, Seluanov A, Mao Z et al. Changes in DNA repair during aging. Nucleic Acids Res 2007; 35:7466–74.
Imam SZ, Karahalil B, Hogue BA et al. Mitochondrial and nuclear DNA-repair capacity of various brain regions in mouse is altered in an age-dependent manner. Neurobiol Aging 2006; 27:1129–36.
Intano GW, Cho EJ, McMahan CA et al. Age-related base excision repair activity in mouse brain and liver nuclear extracts. J Gerontol A Biol Sci Med Sci 2003; 58:205–11.
Lu T, Pan Y, Kao SY et al. Gene regulation and DNA damage in the ageing human brain. Nature 2004; 429:883–91.
Rutten BP, Schmitz C, Gerlach OH et al. The aging brain: accumulation of DNA damage or neuron loss? Neurobiol Aging 2007; 28:91–8.
Katyal S, McKinnon PJ. DNA strand breaks, neurodegeneration and aging in the brain. Mech Ageing Dev 2008; 129:483–91.
Takashima H, Boerkoel CF, John J et al. Mutation of TDP1, encoding a topoisomerase I-dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy. Nat Genet 2002; 32:267–72.
Interthal H, Pouliot JJ, Champoux JJ. The tyrosyl-DNA phosphodiesterase Tdp1 is a member of the phospholipase D superfamily. Proc Natl Acad Sci USA 2001; 98:12009–14.
Interthal H, Chen HJ, Kehl-Fie TE et al. SCAN1 mutant Tdp1 accumulates the enzyme-DNA intermediate and causes camptothecin hypersensitivity. EMBO J 2005; 24:2224–33.
Hirano R, Interthal H, Huang C et al. Spinocerebellar ataxia with axonal neuropathy: consequence of a Tdp1 recessive neomorphic mutation? EMBO J 2007; 26:4732–43.
Pouliot JJ, Yao KC, Robertson CA et al. Yeast gene for a Tyr-DNA phosphodiesterase that repairs topoisomerase I complexes. Science 1999; 286:552–5.
Bertoncini CR, Meneghini R. DNA strand breaks produced by oxidative stress in mammalian cells exhibit 3′-phosphoglycolate termini. Nucleic Acids Res 1995; 23:2995–3002.
Henner WD, Rodriguez LO, Hecht SM et al. Gamma ray induced deoxyribonucleic acid strand breaks. 3′ Glycolate termini. J Biol Chem 1983; 258:711–3.
Povirk LF. DNA damage and mutagenesis by radiomimetic DNA-cleaving agents: bleomycin, neocarzinostatin and other enediynes. Mutat Res 1996; 355:71–89.
Inamdar KV, Pouliot JJ, Zhou T et al. Conversion of phosphoglycolate to phosphate termini on 3′ overhangs of DNA double strand breaks by the human tyrosyl-DNA phosphodiesterase hTdp1. J Biol Chem 2002; 277:27162–8.
Zhou T, Lee JW, Tatavarthi H et al. Deficiency in 3′-phosphoglycolate processing in human cells with a hereditary mutation in tyrosyl-DNA phosphodiesterase (TDP1). Nucleic Acids Res 2005; 33:289–97.
Champoux JJ. DNA topoisomerases: structure, function and mechanism. Annu Rev Biochem 2001; 70:369–413.
Pommier Y, Pourquier P, Fan Y et al. Mechanism of action of eukaryotic DNA topoisomerase I and drugs targeted to the enzyme. Biochim Biophys Acta 1998; 1400:83–105.
Stewart L, Redinbo MR, Qiu X et al. A model for the mechanism of human topoisomerase I. Science 1998; 279:1534–41.
Pommier Y, Redon C, Rao VA et al. Repair of and checkpoint response to topoisomerase I-mediated DNA damage. Mutat Res 2003; 532:173–203.
Pourquier P, Pommier Y. Topoisomerase I-mediated DNA damage. Adv Cancer Res 2001; 80:189–216.
Hsiang YH, Lihou MG, Liu LF. Arrest of replication forks by drug-stabilized topoisomerase I-DNA cleavable complexes as a mechanism of cell killing by camptothecin. Cancer Res 1989; 49:5077–82.
Tsao YP, Russo A, Nyamuswa G et al. Interaction between replication forks and topoisomerase I-DNA cleavable complexes: studies in a cell-free SV40 DNA replication system. Cancer Res 1993; 53:5908–14.
Wu J, Liu LF. Processing of topoisomerase I cleavable complexes into DNA damage by transcription. Nucleic Acids Res 1997; 25:4181–6.
Debethune L, Kohlhagen G, Grandas A et al. Processing of nucleopeptides mimicking the topoisomerase I-DNA covalent complex by tyrosyl-DNA phosphodiesterase. Nucleic Acids Res 2002; 30:1198–204.
El-Khamisy SF, Saifi GM, Weinfeld M et al. Defective DNA single-strand break repair in spinocerebellar ataxia with axonal neuropathy-1. Nature 2005; 434:108–13.
Yang SW, Burgin AB Jr, Huizenga BN et al. A eukaryotic enzyme that can disjoin dead-end covalent complexes between DNA and type I topoisomerases. Proc Natl Acad Sci USA 1996; 93:11534–9.
Interthal H, Chen HJ, Champoux JJ. Human Tdp1 cleaves a broad spectrum of substrates, including phosphoamide linkages. J Biol Chem 2005; 280:36518–28.
Ponting CP, Kerr ID. A novel family of phospholipase D homologues that includes phospholipid synthases and putative endonucleases: identification of duplicated repeats and potential active site residues. Protein Sci 1996; 5:914–22.
Stuckey JA, Dixon JE. Crystal structure of a phospholipase D family member. Nat Struct Biol 1999; 6:278–84.
Davies DR, Interthal H, Champoux JJ et al. The crystal structure of human tyrosyl-DNA phosphodiesterase, Tdp1. Structure (Camb) 2002; 10:237–48.
Raymond AC, Rideout MC, Staker B et al. Analysis of human tyrosyl-DNA phosphodiesterase I catalytic residues. J Mol Biol 2004; 338:895–906.
Davies DR, Interthal H, Champoux JJ et al. Insights into substrate binding and catalytic mechanism of human tyrosyl-DNA phosphodiesterase (Tdp1) from vanadate and tungstate-inhibited structures. J Mol Biol 2002; 324:917–32.
Hawkins AJ, Subler MA, Akopiants K et al. In vitro complementation of Tdp1 deficiency indicates a stabilized enzyme-DNA adduct from tyrosyl but not glycolate lesions as a consequence of the SCAN1 mutation. DNA Repair (Amst) 2009; 8:654–63.
Katyal S, el-Khamisy SF, Russell HR et al. TDP1 facilitates chromosomal single-strand break repair in neurons and is neuroprotective in vivo. EMBO J 2007; 26:4720–31.
Deng C, Brown JA, You D et al. Multiple endonucleases function to repair covalent topoisomerase I complexes in Saccharomyces cerevisiae. Genetics 2005; 170:591–600.
Dunlop J, Morin X, Corominas M et al. glaikit is essential for the formation of epithelial polarity and neuronal development. Curr Biol 2004; 14:2039–45.
Liu C, Pouliot JJ, Nash HA. Repair of topoisomerase I covalent complexes in the absence of the tyrosyl-DNA phosphodiesterase Tdp1. Proc Natl Acad Sci USA 2002; 99:14970–5.
Vance JR, Wilson TE. Yeast Tdp1 and Rad1-Rad10 function as redundant pathways for repairing Top1 replicative damage. Proc Natl Acad Sci USA 2002; 99:13669–74.
El-Khamisy SF, Katyal S, Patel P et al. Synergistic decrease of DNA single-strand break repair rates in mouse neural cells lacking both Tdp1 and aprataxin. DNA Repair (Amst) 2009; 8:760–6.
Liu C, Zhou S, Begum S et al. Increased expression and activity of repair genes TDP1 and XPF in nonsmall cell lung cancer. Lung Cancer 2007; 55:303–11.
McKinnon PJ, Caldecott KW. DNA strand break repair and human genetic disease. Annu Rev Genomics Hum Genet 2007; 8:37–55.
Dexheimer TS, Antony S, Marchand C et al. Tyrosyl-DNA phosphodiesterase as a target for anticancer therapy. Anticancer Agents Med Chem 2008; 8:381–9.
Turashvili G, Kalloger S, Gelmon K et al. Subcellular protein expression pattern of the DNA repair enzyme Tdp1 is prognostic in breast cancer 2009. In Press.
Davies DR, Interthal H, Champoux JJ et al. Crystal structure of a transition state mimic for Tdp1 assembled from vanadate, DNA and a topoisomerase I-derived peptide. Chem Biol 2003; 10:139–47.
Davies DR, Interthal H, Champoux JJ et al. Explorations of peptide and oligonucleotide binding sites of tyrosyl-DNA phosphodiesterase using vanadate complexes. J Med Chem 2004; 47:829–37.
Liao Z, Thibaut L, Jobson A et al. Inhibition of human tyrosyl-DNA phosphodiesterase by aminoglycoside antibiotics and ribosome inhibitors. Mol Pharmacol 2006; 70:366–72.
Antony S, Marchand C, Stephen AG et al. Novel high-throughput electrochemiluminescent assay for identification of human tyrosyl-DNA phosphodiesterase (Tdp1) inhibitors and characterization of furamidine (NSC 305831) as an inhibitor of Tdp1. Nucleic Acids Res 2007; 35:4474–84.
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Walton, C., Interthal, H., Hirano, R., Salih, M.A.M., Takashima, H., Boerkoel, C.F. (2010). Spinocerebellar Ataxia with Axonal Neuropathy. In: Ahmad, S.I. (eds) Diseases of DNA Repair. Advances in Experimental Medicine and Biology, vol 685. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-6448-9_7
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DOI: https://doi.org/10.1007/978-1-4419-6448-9_7
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