The Role of the Mammalian DNA End-processing Enzyme Polynucleotide Kinase 3’-Phosphatase in Spinocerebellar Ataxia Type 3 Pathogenesis

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We report that human polynucleotide kinase 3’-phosphatase (PNKP), a major DNA strand break repair enzyme, stably associates with Ataxin-3 (ATXN3). This protein contains repeats of the amino acid glutamine, and the expansion of these repeats from 14–41 to 55–82 glutamines leads to a neurological disorder called Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease (MJD). However, how this expansion of glutamine leads to ataxia has remained unclear. Here we show that normal ATXN3 protein stimulates, but the expanded ATXN3 inhibits, PNKP’s DNA repair activity, causing an accumulation of DNA damage. Furthermore, a SCA3 mouse model showed decreased PNKP activity, mostly in a region that is highly affected in MJD patients’ brains. Analysis of human MJD patients’ neuronal DNA showed significant accumulation of DNA strand breaks. Collectively, the accumulation of DNA damage due to decreased PNKP repair activity is likely to induce neuronal cell death, a hallmark of SCA3/MJD pathogenesis.

Vyšlo v časopise: The Role of the Mammalian DNA End-processing Enzyme Polynucleotide Kinase 3’-Phosphatase in Spinocerebellar Ataxia Type 3 Pathogenesis. PLoS Genet 11(1): e32767. doi:10.1371/journal.pgen.1004749
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004749

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1. Date H, Onodera O, Tanaka H, Iwabuchi K, Uekawa K, et al. (2001) Early-onset ataxia with ocular motor apraxia and hypoalbuminemia is caused by mutations in a new HIT superfamily gene. Nat Genet 29: 184–188. doi: 10.1038/ng1001-184 11586299

2. Moreira MC, Barbot C, Tachi N, Kozuka N, Uchida E, et al. (2001) The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT/Zn-finger protein aprataxin. Nat Genet 29: 189–193. doi: 10.1038/ng1001-189 11586300

3. Takashima H, Boerkoel CF, John J, Saifi GM, Salih MA, et al. (2002) Mutation of TDP1, encoding a topoisomerase I-dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy. Nat Genet 32: 267–272. doi: 10.1038/ng987 12244316

4. Katyal S, el-Khamisy SF, Russell HR, Li Y, Ju L, et al. (2007) TDP1 facilitates chromosomal single-strand break repair in neurons and is neuroprotective in vivo. Embo J 26: 4720–4731. doi: 10.1038/sj.emboj.7601869 17914460

5. Jilani A, Ramotar D, Slack C, Ong C, Yang XM, et al. (1999) Molecular cloning of the human gene, PNKP, encoding a polynucleotide kinase 3’-phosphatase and evidence for its role in repair of DNA strand breaks caused by oxidative damage. J Biol Chem 274: 24176–24186. doi: 10.1074/jbc.274.34.24176 10446192

6. Karimi-Busheri F, Daly G, Robins P, Canas B, Pappin DJ, et al. (1999) Molecular characterization of a human DNA kinase. J Biol Chem 274: 24187–24194. doi: 10.1074/jbc.274.34.24187 10446193

7. Das A, Wiederhold L, Leppard JB, Kedar P, Prasad R, et al. (2006) NEIL2-initiated, APE-independent repair of oxidized bases in DNA: Evidence for a repair complex in human cells. DNA Repair (Amst) 5: 1439–1448. doi: 10.1016/j.dnarep.2006.07.003 16982218

8. Plo I, Liao ZY, Barcelo JM, Kohlhagen G, Caldecott KW, et al. (2003) Association of XRCC1 and tyrosyl DNA phosphodiesterase (Tdp1) for the repair of topoisomerase I-mediated DNA lesions. DNA Repair (Amst) 2: 1087–1100. doi: 10.1016/S1568-7864(03)00116-2 13679147

9. Shen J, Gilmore EC, Marshall CA, Haddadin M, Reynolds JJ, et al. (2010) Mutations in PNKP cause microcephaly, seizures and defects in DNA repair. Nat Genet 42: 245–249. doi: 10.1038/ng.526 20118933

10. Poulton C, Oegema R, Heijsman D, Hoogeboom J, Schot R, et al. (2012) Progressive cerebellar atrophy and polyneuropathy: expanding the spectrum of PNKP mutations. Neurogenetics.

11. Caldecott KW (2001) Mammalian DNA single-strand break repair: an X-ra(y)ted affair. Bioessays 23: 447–455. doi: 10.1002/bies.1063 11340626

12. Caldecott KW (2008) Single-strand break repair and genetic disease. Nat Rev Genet 9: 619–631. doi: 10.1038/nrg2380 18626472

13. Ljungman M, Zhang F (1996) Blockage of RNA polymerase as a possible trigger for u.v. light-induced apoptosis. Oncogene 13: 823–831. 8761304

14. McKinnon PJ (2013) Maintaining genome stability in the nervous system. Nat Neurosci 16: 1523–1529. doi: 10.1038/nn.3537 24165679

15. Costa MC, Gomes-da-Silva J, Miranda CJ, Sequeiros J, Santos MM, et al. (2004) Genomic structure, promoter activity, and developmental expression of the mouse homologue of the Machado-Joseph disease (MJD) gene. Genomics 84: 361–373. doi: 10.1016/j.ygeno.2004.02.012 15233999

16. Paulson HL, Das SS, Crino PB, Perez MK, Patel SC, et al. (1997) Machado-Joseph disease gene product is a cytoplasmic protein widely expressed in brain. Ann Neurol 41: 453–462. doi: 10.1002/ana.410410408 9124802

17. Schmidt T, Landwehrmeyer GB, Schmitt I, Trottier Y, Auburger G, et al. (1998) An isoform of ataxin-3 accumulates in the nucleus of neuronal cells in affected brain regions of SCA3 patients. Brain Pathol 8: 669–679. doi: 10.1111/j.1750-3639.1998.tb00193.x 9804376

18. Trottier Y, Cancel G, An-Gourfinkel I, Lutz Y, Weber C, et al. (1998) Heterogeneous intracellular localization and expression of ataxin-3. Neurobiol Dis 5: 335–347. doi: 10.1006/nbdi.1998.0208 10069576

19. Li F, Macfarlan T, Pittman RN, Chakravarti D (2002) Ataxin-3 is a histone-binding protein with two independent transcriptional corepressor activities. J Biol Chem 277: 45004–45012. doi: 10.1074/jbc.M205259200 12297501

20. Burnett BG, Pittman RN (2005) The polyglutamine neurodegenerative protein ataxin 3 regulates aggresome formation. Proc Natl Acad Sci U S A 102: 4330–4335. doi: 10.1073/pnas.0407252102 15767577

21. Warrick JM, Morabito LM, Bilen J, Gordesky-Gold B, Faust LZ, et al. (2005) Ataxin-3 suppresses polyglutamine neurodegeneration in Drosophila by a ubiquitin-associated mechanism. Mol Cell 18: 37–48. doi: 10.1016/j.molcel.2005.02.030 15808507

22. Winborn BJ, Travis SM, Todi SV, Scaglione KM, Xu P, et al. (2008) The deubiquitinating enzyme ataxin-3, a polyglutamine disease protein, edits Lys63 linkages in mixed linkage ubiquitin chains. J Biol Chem 283: 26436–26443. doi: 10.1074/jbc.M803692200 18599482

23. Kawaguchi Y, Okamoto T, Taniwaki M, Aizawa M, Inoue M, et al. (1994) CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet 8: 221–228. doi: 10.1038/ng1194-221 7874163

24. Schols L, Bauer P, Schmidt T, Schulte T, Riess O (2004) Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis. Lancet Neurol 3: 291–304. doi: 10.1016/S1474-4422(04)00737-9 15099544

25. Paulson H Machado-Joseph disease/spinocerebellar ataxia type 3. Handb Clin Neurol 103: 437–449. doi: 10.1016/B978-0-444-51892-7.00027-9 21827905

26. Banerjee D, Mandal SM, Das A, Hegde ML, Das S, et al. (2011) Preferential repair of oxidized base damage in the transcribed genes of Mammalian cells. J Biol Chem 286: 6006–6016. doi: 10.1074/jbc.M110.198796 21169365

27. Hegde ML, Hegde PM, Bellot LJ, Mandal SM, Hazra TK, et al. (2013) Prereplicative repair of oxidized bases in the human genome is mediated by NEIL1 DNA glycosylase together with replication proteins. Proc Natl Acad Sci U S A 110: E3090–3099. doi: 10.1073/pnas.1304231110 23898192

28. Cook PR (1999) The organization of replication and transcription. Science 284: 1790–1795. doi: 10.1126/science.284.5421.1790 10364545

29. Wang G, Sawai N, Kotliarova S, Kanazawa I, Nukina N (2000) Ataxin-3, the MJD1 gene product, interacts with the two human homologs of yeast DNA repair protein RAD23, HHR23A and HHR23B. Hum Mol Genet 9: 1795–1803. doi: 10.1093/hmg/9.12.1795 10915768

30. Whitehouse CJ, Taylor RM, Thistlethwaite A, Zhang H, Karimi-Busheri F, et al. (2001) XRCC1 stimulates human polynucleotide kinase activity at damaged DNA termini and accelerates DNA single-strand break repair. Cell 104: 107–117. doi: 10.1016/S0092-8674(01)00195-7 11163244

31. Fredriksson S, Gullberg M, Jarvius J, Olsson C, Pietras K, et al. (2002) Protein detection using proximity-dependent DNA ligation assays. Nat Biotechnol 20: 473–477. doi: 10.1038/nbt0502-473 11981560

32. Soderberg O, Gullberg M, Jarvius M, Ridderstrale K, Leuchowius KJ, et al. (2006) Direct observation of individual endogenous protein complexes in situ by proximity ligation. Nat Methods 3: 995–1000. doi: 10.1038/nmeth947 17072308

33. Dey S, Maiti AK, Hegde ML, Hegde PM, Boldogh I, et al. (2012) Increased risk of lung cancer associated with a functionally impaired polymorphic variant of the human DNA glycosylase NEIL2. DNA Repair (Amst) 11: 570–578. doi: 10.1016/j.dnarep.2012.03.005 22497777

34. Ayala-Torres S, Chen Y, Svoboda T, Rosenblatt J, Van Houten B (2000) Analysis of gene-specific DNA damage and repair using quantitative polymerase chain reaction. Methods 22: 135–147. doi: 10.1006/meth.2000.1054 11020328

35. Evert BO, Wullner U, Schulz JB, Weller M, Groscurth P, et al. (1999) High level expression of expanded full-length ataxin-3 in vitro causes cell death and formation of intranuclear inclusions in neuronal cells. Hum Mol Genet 8: 1169–1176. doi: 10.1093/hmg/8.7.1169 10369861

36. Silva-Fernandes A, Costa Mdo C, Duarte-Silva S, Oliveira P, Botelho CM, et al. (2010) Motor uncoordination and neuropathology in a transgenic mouse model of Machado-Joseph disease lacking intranuclear inclusions and ataxin-3 cleavage products. Neurobiol Dis 40: 163–176. doi: 10.1016/j.nbd.2010.05.021 20510362

37. Silva-Fernandes A, Duarte-Silva S, Neves-Carvalho A, Amorim M, Soares-Cunha C, et al. (2014) Chronic treatment with 17-DMAG improves balance and coordination in a new mouse model of Machado-Joseph disease. Neurotherapeutics 11: 433–449. doi: 10.1007/s13311-013-0255-9 24477711

38. Santos JH, Meyer JN, Mandavilli BS, Van Houten B (2006) Quantitative PCR-based measurement of nuclear and mitochondrial DNA damage and repair in mammalian cells. Methods Mol Biol 314: 183–199. 16673882

39. Chai Y, Berke SS, Cohen RE, Paulson HL (2004) Poly-ubiquitin binding by the polyglutamine disease protein ataxin-3 links its normal function to protein surveillance pathways. J Biol Chem 279: 3605–3611. doi: 10.1074/jbc.M310939200 14602712

40. Doss-Pepe EW, Stenroos ES, Johnson WG, Madura K (2003) Ataxin-3 interactions with rad23 and valosin-containing protein and its associations with ubiquitin chains and the proteasome are consistent with a role in ubiquitin-mediated proteolysis. Mol Cell Biol 23: 6469–6483. doi: 10.1128/MCB.23.18.6469-6483.2003 12944474

41. Burnett B, Li F, Pittman RN (2003) The polyglutamine neurodegenerative protein ataxin-3 binds polyubiquitylated proteins and has ubiquitin protease activity. Hum Mol Genet 12: 3195–3205. doi: 10.1093/hmg/ddg344 14559776

42. Mao Y, Senic-Matuglia F, Di Fiore PP, Polo S, Hodsdon ME, et al. (2005) Deubiquitinating function of ataxin-3: insights from the solution structure of the Josephin domain. Proc Natl Acad Sci U S A 102: 12700–12705. doi: 10.1073/pnas.0506344102 16118278

43. Schmitt I, Linden M, Khazneh H, Evert BO, Breuer P, et al. (2007) Inactivation of the mouse Atxn3 (ataxin-3) gene increases protein ubiquitination. Biochem Biophys Res Commun 362: 734–739. doi: 10.1016/j.bbrc.2007.08.062 17764659

44. Klement IA, Skinner PJ, Kaytor MD, Yi H, Hersch SM, et al. (1998) Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice. Cell 95: 41–53. doi: 10.1016/S0092-8674(00)81781-X 9778246

45. Saudou F, Finkbeiner S, Devys D, Greenberg ME (1998) Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 95: 55–66. doi: 10.1016/S0092-8674(00)81782-1 9778247

46. Zhou L, Wang H, Wang P, Ren H, Chen D, et al. (2013) Ataxin-3 protects cells against H2O2-induced oxidative stress by enhancing the interaction between Bcl-X(L) and Bax. Neuroscience 243: 14–21. doi: 10.1016/j.neuroscience.2013.03.047 23562578

47. Parsons JL, Khoronenkova SV, Dianova II, Ternette N, Kessler BM, et al. (2012) Phosphorylation of PNKP by ATM prevents its proteasomal degradation and enhances resistance to oxidative stress. Nucleic Acids Res 40: 11404–11415. doi: 10.1093/nar/gks909 23042680

48. Segal-Raz H, Mass G, Baranes-Bachar K, Lerenthal Y, Wang SY, et al. (2011) ATM-mediated phosphorylation of polynucleotide kinase/phosphatase is required for effective DNA double-strand break repair. EMBO Rep 12: 713–719. doi: 10.1038/embor.2011.96 21637298

49. Zolner AE, Abdou I, Ye R, Mani RS, Fanta M, et al. (2011) Phosphorylation of polynucleotide kinase/ phosphatase by DNA-dependent protein kinase and ataxia-telangiectasia mutated regulates its association with sites of DNA damage. Nucleic Acids Res 39: 9224–9237. doi: 10.1093/nar/gkr647 21824916

50. Suberbielle E, Sanchez PE, Kravitz AV, Wang X, Ho K, et al. (2013) Physiologic brain activity causes DNA double-strand breaks in neurons, with exacerbation by amyloid-beta. Nat Neurosci 16: 613–621. doi: 10.1038/nn.3356 23525040

51. Liu W, Jiang F, Bi X, Zhang YQ (2012) Drosophila FMRP participates in the DNA damage response by regulating G2/M cell cycle checkpoint and apoptosis. Hum Mol Genet 21: 4655–4668. doi: 10.1093/hmg/dds307 22843500

52. Alpatov R, Lesch BJ, Nakamoto-Kinoshita M, Blanco A, Chen S, et al. (2014) A chromatin-dependent role of the fragile X mental retardation protein FMRP in the DNA damage response. Cell 157: 869–881. doi: 10.1016/j.cell.2014.03.040 24813610

53. Zhang W, Cheng Y, Li Y, Chen Z, Jin P, et al. (2014) A feed-forward mechanism involving Drosophila fragile X mental retardation protein triggers a replication stress-induced DNA damage response. Hum Mol Genet 23: 5188–5196. doi: 10.1093/hmg/ddu241 24833720

54. Pearson CE, Nichol Edamura K, Cleary JD (2005) Repeat instability: mechanisms of dynamic mutations. Nat Rev Genet 6: 729–742. doi: 10.1038/nrg1689 16205713

55. Lopez Castel A, Cleary JD, Pearson CE (2010) Repeat instability as the basis for human diseases and as a potential target for therapy. Nat Rev Mol Cell Biol 11: 165–170. doi: 10.1038/nrm2854 20177394

56. Mason AG, Tome S, Simard JP, Libby RT, Bammler TK, et al. (2014) Expression levels of DNA replication and repair genes predict regional somatic repeat instability in the brain but are not altered by polyglutamine disease protein expression or age. Hum Mol Genet 23: 1606–1618. doi: 10.1093/hmg/ddt551 24191263

57. Aygun O, Svejstrup J, Liu Y (2008) A RECQ5-RNA polymerase II association identified by targeted proteomic analysis of human chromatin. Proc Natl Acad Sci U S A 105: 8580–8584. doi: 10.1073/pnas.0804424105 18562274

58. Mandal SM, Hegde ML, Chatterjee A, Hegde PM, Szczesny B, et al. (2012) Role of human DNA glycosylase Nei-like 2 (NEIL2) and single strand break repair protein polynucleotide kinase 3’-phosphatase in maintenance of mitochondrial genome. J Biol Chem 287: 2819–2829. doi: 10.1074/jbc.M111.272179 22130663

59. Wiederhold L, Leppard JB, Kedar P, Karimi-Busheri F, Rasouli-Nia A, et al. (2004) AP endonuclease-independent DNA base excision repair in human cells. Mol Cell 15: 209–220. doi: 10.1016/j.molcel.2004.06.003 15260972

60. Kovtun IV, Liu Y, Bjoras M, Klungland A, Wilson SH, et al. (2007) OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells. Nature 447: 447–452. doi: 10.1038/nature05778 17450122

61. Das A, Boldogh I, Lee JW, Harrigan JA, Hegde ML, et al. (2007) The human Werner syndrome protein stimulates repair of oxidative DNA base damage by the DNA glycosylase NEIL1. J Biol Chem 282: 26591–26602. doi: 10.1074/jbc.M703343200 17611195

62. Dignam JD, Lebovitz RM, Roeder RG (1983) Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res 11: 1475–1489 doi: 10.1093/nar/11.5.1475 6828386