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Topoisomerases and the regulation of neural function

Nature Reviews Neuroscience volume 17, pages 673–679 (2016)Cite this article

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Abstract

Topoisomerases are unique enzymes that regulate torsional stress in DNA to enable essential genome functions, including DNA replication and transcription. Although all cells in an organism require topoisomerases to maintain normal function, the nervous system in particular shows a vital need for these enzymes. Indeed, a range of inherited human neurologic syndromes, including neurodegeneration, schizophrenia and intellectual impairment, are associated with aberrant topoisomerase function. Much remains unknown regarding the tissue-specific function of neural topoisomerases or the connections between these enzymes and disease aetiology. Precisely how topoisomerases regulate genome dynamics within the nervous system is therefore a crucial research question.

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Figure 1: Mammalian topoisomerases.
Figure 2: Topoisomerase function.

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References

  1. Gartenberg, M. R. & Wang, J. C. Positive supercoiling of DNA greatly diminishes mRNA synthesis in yeast. Proc. Natl Acad. Sci. USA 89, 11461–11465 (1992).

    Article  CAS  Google Scholar 

  2. Joshi, R. S., Pina, B. & Roca, J. Positional dependence of transcriptional inhibition by DNA torsional stress in yeast chromosomes. EMBO J. 29, 740–748 (2010).

    Article  CAS  Google Scholar 

  3. Bermejo, R., Lai, M. S. & Foiani, M. Preventing replication stress to maintain genome stability: resolving conflicts between replication and transcription. Mol. Cell 45, 710–718 (2012).

    Article  CAS  Google Scholar 

  4. McClendon, A. K., Rodriguez, A. C. & Osheroff, N. Human topoisomerase IIα rapidly relaxes positively supercoiled DNA: implications for enzyme action ahead of replication forks. J. Biol. Chem. 280, 39337–39345 (2005).

    Article  CAS  Google Scholar 

  5. Vos, S. M., Tretter, E. M., Schmidt, B. H. & Berger, J. M. All tangled up: how cells direct, manage and exploit topoisomerase function. Nat. Rev. Mol. Cell Biol. 12, 827–841 (2011).

    Article  CAS  Google Scholar 

  6. Wang, J. C. Cellular roles of DNA topoisomerases: a molecular perspective. Nat. Rev. Mol. Cell Biol. 3, 430–440 (2002).

    Article  CAS  Google Scholar 

  7. Champoux, J. J. DNA topoisomerases: structure, function, and mechanism. Annu. Rev. Biochem. 70, 369–413 (2001).

    Article  CAS  Google Scholar 

  8. Nitiss, J. L. DNA topoisomerase II and its growing repertoire of biological functions. Nat. Rev. Cancer 9, 327–337 (2009).

    Article  CAS  Google Scholar 

  9. Pommier, Y. et al. Repair of topoisomerase I-mediated DNA damage. Prog. Nucleic Acid. Res. Mol. Biol. 81, 179–229 (2006).

    Article  CAS  Google Scholar 

  10. Mondal, N. & Parvin, J. D. DNA topoisomerase IIα is required for RNA polymerase II transcription on chromatin templates. Nature 413, 435–438 (2001).

    Article  CAS  Google Scholar 

  11. Pedersen, J. M. et al. DNA topoisomerases maintain promoters in a state competent for transcriptional activation in Saccharomyces cerevisiae. PLoS Genet. 8, e1003128 (2012).

    Article  Google Scholar 

  12. Zhang, H., Wang, J. C. & Liu, L. F. Involvement of DNA topoisomerase I in transcription of human ribosomal RNA genes. Proc. Natl Acad. Sci. USA 85, 1060–1064 (1988).

    Article  CAS  Google Scholar 

  13. Andersen, S. L., Sloan, R. S., Petes, T. D. & Jinks-Robertson, S. Genome-destabilizing effects associated with Top1 loss or accumulation of Top1 cleavage complexes in yeast. PLoS Genet. 11, e1005098 (2015).

    Article  Google Scholar 

  14. Chen, S. H., Chan, N. L. & Hsieh, T. S. New mechanistic and functional insights into DNA topoisomerases. Annu. Rev. Biochem. 82, 139–170 (2013).

    Article  CAS  Google Scholar 

  15. Takashima, H. et al. Mutation of TDP1, encoding a topoisomerase I–dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy. Nat. Genet. 32, 267–272 (2002).

    Article  CAS  Google Scholar 

  16. McKinnon, P. J. Maintaining genome stability in the nervous system. Nat. Neurosci. 16, 1523–1529 (2013).

    Article  CAS  Google Scholar 

  17. Gómez-Herreros, F. et al. TDP2 protects transcription from abortive topoisomerase activity and is required for normal neural function. Nat. Genet. 46, 516–521 (2014).

    Article  Google Scholar 

  18. Stoll, G. et al. Deletion of TOP3β, a component of FMRP-containing mRNPs, contributes to neurodevelopmental disorders. Nat. Neurosci. 16, 1228–1237 (2013).

    Article  CAS  Google Scholar 

  19. Xu, D. et al. Top3β is an RNA topoisomerase that works with fragile X syndrome protein to promote synapse formation. Nat. Neurosci. 16, 1238–1247 (2013).

    Article  CAS  Google Scholar 

  20. Akimitsu, N. et al. Enforced cytokinesis without complete nuclear division in embryonic cells depleting the activity of DNA topoisomerase IIα. Genes Cells 8, 393–402 (2003).

    Article  CAS  Google Scholar 

  21. Li, W. & Wang, J. C. Mammalian DNA topoisomerase IIIα is essential in early embryogenesis. Proc. Natl Acad. Sci. USA 95, 1010–1013 (1998).

    Article  CAS  Google Scholar 

  22. Morham, S. G., Kluckman, K. D., Voulomanos, N. & Smithies, O. Targeted disruption of the mouse topoisomerase I gene by camptothecin selection. Mol. Cell. Biol. 16, 6804–6809 (1996).

    Article  CAS  Google Scholar 

  23. King, I. F. et al. Topoisomerases facilitate transcription of long genes linked to autism. Nature 501, 58–62 (2013).

    Article  CAS  Google Scholar 

  24. Lyu, Y. L. et al. Role of topoisomerase IIβ in the expression of developmentally regulated genes. Mol. Cell. Biol. 26, 7929–7941 (2006).

    Article  CAS  Google Scholar 

  25. Madabhushi, R. et al. Activity-induced DNA breaks govern the expression of neuronal early-response genes. Cell 161, 1592–1605 (2015).

    Article  CAS  Google Scholar 

  26. Keeney, S. Spo11 and the formation of DNA double-strand breaks in meiosis. Genome Dyn. Stab. 2, 81–123 (2008).

    Article  Google Scholar 

  27. Douarre, C. et al. Mitochondrial topoisomerase I is critical for mitochondrial integrity and cellular energy metabolism. PLoS ONE 7, e41094 (2012).

    Article  CAS  Google Scholar 

  28. Zhang, H. et al. Human mitochondrial topoisomerase I. Proc. Natl Acad. Sci. USA 98, 10608–10613 (2001).

    Article  CAS  Google Scholar 

  29. Linka, R. M. et al. C-Terminal regions of topoisomerase IIα and IIβ determine isoform-specific functioning of the enzymes in vivo. Nucleic Acids Res. 35, 3810–3822 (2007).

    Article  CAS  Google Scholar 

  30. Zhang, H. et al. Increased negative supercoiling of mtDNA in TOP1mt knockout mice and presence of topoisomerases IIα and IIβ in vertebrate mitochondria. Nucleic Acids Res. 42, 7259–7267 (2014).

    Article  CAS  Google Scholar 

  31. Wang, Y., Lyu, Y. L. & Wang, J. C. Dual localization of human DNA topoisomerase IIIα to mitochondria and nucleus. Proc. Natl Acad. Sci. USA 99, 12114–12119 (2002).

    Article  CAS  Google Scholar 

  32. Yang, X., Li, W., Prescott, E. D., Burden, S. J. & Wang, J. C. DNA topoisomerase IIβ and neural development. Science 287, 131–134 (2000).

    Article  CAS  Google Scholar 

  33. Kwan, K. Y. & Wang, J. C. Mice lacking DNA topoisomerase IIIβ develop to maturity but show a reduced mean lifespan. Proc. Natl Acad. Sci. USA 98, 5717–5721 (2001).

    Article  CAS  Google Scholar 

  34. Khiati, S. et al. Lack of mitochondrial topoisomerase I (TOP1mt) impairs liver regeneration. Proc. Natl Acad. Sci. USA 112, 11282–11287 (2015).

    Article  CAS  Google Scholar 

  35. Ciccia, A. & Elledge, S. J. The DNA damage response: making it safe to play with knives. Mol. Cell 40, 179–204 (2010).

    Article  CAS  Google Scholar 

  36. Lin, C. P., Ban, Y., Lyu, Y. L., Desai, S. D. & Liu, L. F. A ubiquitin-proteasome pathway for the repair of topoisomerase I-DNA covalent complexes. J. Biol. Chem. 283, 21074–21083 (2008).

    Article  CAS  Google Scholar 

  37. Mao, Y., Sun, M., Desai, S. D. & Liu, L. F. SUMO-1 conjugation to topoisomerase I: a possible repair response to topoisomerase-mediated DNA damage. Proc. Natl Acad. Sci. USA 97, 4046–4051 (2000).

    Article  CAS  Google Scholar 

  38. Ashour, M. E., Atteya, R. & El-Khamisy, S. F. Topoisomerase-mediated chromosomal break repair: an emerging player in many games. Nat. Rev. Cancer 15, 137–151 (2015).

    Article  CAS  Google Scholar 

  39. Caldecott, K. W. Single-strand break repair and genetic disease. Nat. Rev. Genet. 9, 619–631 (2008).

    Article  CAS  Google Scholar 

  40. Pommier, Y. et al. Tyrosyl-DNA-phosphodiesterases (TDP1 and TDP2). DNA Repair (Amst.) 19, 114–129 (2014).

    Article  CAS  Google Scholar 

  41. Gomez-Herreros, F. et al. TDP2-dependent non-homologous end-joining protects against topoisomerase II-induced DNA breaks and genome instability in cells and in vivo. PLoS Genet. 9, e1003226 (2013).

    Article  CAS  Google Scholar 

  42. Nitiss, J. L. & Nitiss, K. C. Tdp2: a means to fixing the ends. PLoS Genet. 9, e1003370 (2013).

    Article  CAS  Google Scholar 

  43. El-Khamisy, S. F. et al. Defective DNA single-strand break repair in spinocerebellar ataxia with axonal neuropathy-1. Nature 434, 108–113 (2005).

    Article  CAS  Google Scholar 

  44. Cortes Ledesma, F., El Khamisy, S. F., Zuma, M. C., Osborn, K. & Caldecott, K. W. A human 5′-tyrosyl DNA phosphodiesterase that repairs topoisomerase-mediated DNA damage. Nature 461, 674–678 (2009).

    Article  Google Scholar 

  45. McKinnon, P. J. DNA repair deficiency and neurological disease. Nat. Rev. Neurosci. 10, 100–112 (2009).

    Article  CAS  Google Scholar 

  46. Zylka, M. J., Simon, J. M. & Philpot, B. D. Gene length matters in neurons. Neuron 86, 353–355 (2015).

    Article  CAS  Google Scholar 

  47. Tsutsui, K., Tsutsui, K., Sano, K., Kikuchi, A. & Tokunaga, A. Involvement of DNA topoisomerase IIβ in neuronal differentiation. J. Biol. Chem. 276, 5769–5778 (2001).

    Article  CAS  Google Scholar 

  48. Lyu, Y. L. & Wang, J. C. Aberrant lamination in the cerebral cortex of mouse embryos lacking DNA topoisomerase IIβ. Proc. Natl Acad. Sci. USA 100, 7123–7128 (2003).

    Article  CAS  Google Scholar 

  49. Mabb, A. M. et al. Topoisomerase 1 regulates gene expression in neurons through cleavage complex-dependent and -independent mechanisms. PLoS ONE 11, e0156439 (2016).

    Article  Google Scholar 

  50. Plaschkes, I., Silverman, F. W. & Priel, E. DNA topoisomerase I in the mouse central nervous system: age and sex dependence. J. Comp. Neurol. 493, 357–369 (2005).

    Article  CAS  Google Scholar 

  51. Katyal, S. et al. Aberrant topoisomerase-1 DNA lesions are pathogenic in neurodegenerative genome instability syndromes. Nat. Neurosci. 17, 813–821 (2014).

    Article  CAS  Google Scholar 

  52. Zehorai, E., Eitan, E., Hershfinkel, M., Sekler, I. & Priel, E. Glutamate regulates the activity of topoisomerase I in mouse cerebellum. Mol. Neurobiol. 38, 242–252 (2008).

    Article  CAS  Google Scholar 

  53. Tiwari, V. K. et al. Target genes of topoisomerase IIβ regulate neuronal survival and are defined by their chromatin state. Proc. Natl Acad. Sci. USA 109, E934–E943 (2012).

    Article  CAS  Google Scholar 

  54. Li, Y. et al. Topoisomerase IIβ is required for proper retinal development and survival of postmitotic cells. Biol. Open 3, 172–184 (2014).

    Article  CAS  Google Scholar 

  55. Bunch, H. et al. Transcriptional elongation requires DNA break-induced signalling. Nat. Commun. 6, 10191 (2015).

    Article  CAS  Google Scholar 

  56. Ju, B. G. et al. A topoisomerase IIβ-mediated dsDNA break required for regulated transcription. Science 312, 1798–1802 (2006).

    Article  CAS  Google Scholar 

  57. Heinz, S., Romanoski, C. E., Benner, C. & Glass, C. K. The selection and function of cell type-specific enhancers. Nat. Rev. Mol. Cell Biol. 16, 144–154 (2015).

    Article  CAS  Google Scholar 

  58. Puc, J. et al. Ligand-dependent enhancer activation regulated by topoisomerase-I activity. Cell 160, 367–380 (2015).

    Article  CAS  Google Scholar 

  59. Mabb, A. M. et al. Topoisomerase 1 inhibition reversibly impairs synaptic function. Proc. Natl Acad. Sci. USA 111, 17290–17295 (2014).

    Article  CAS  Google Scholar 

  60. Gabel, H. W. et al. Disruption of DNA-methylation-dependent long gene repression in Rett syndrome. Nature 522, 89–93 (2015).

    Article  CAS  Google Scholar 

  61. Sugino, K. et al. Cell-type-specific repression by methyl-CpG-binding protein 2 is biased toward long genes. J. Neurosci. 34, 12877–12883 (2014).

    Article  CAS  Google Scholar 

  62. Huang, H. S. et al. Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons. Nature 481, 185–189 (2012).

    Article  CAS  Google Scholar 

  63. Powell, W. T. et al. R-Loop formation at Snord116 mediates topotecan inhibition of Ube3a-antisense and allele-specific chromatin decondensation. Proc. Natl Acad. Sci. USA 110, 13938–13943 (2013).

    Article  CAS  Google Scholar 

  64. McKinnon, P. J. ATM and the molecular pathogenesis of ataxia telangiectasia. Annu. Rev. Pathol. 7, 303–321 (2012).

    Article  CAS  Google Scholar 

  65. Hansen, T. B. et al. Natural RNA circles function as efficient microRNA sponges. Nature 495, 384–388 (2013).

    Article  CAS  Google Scholar 

  66. Lasda, E. & Parker, R. Circular RNAs: diversity of form and function. RNA 20, 1829–1842 (2014).

    Article  CAS  Google Scholar 

  67. Memczak, S. et al. Circular RNAs are a large class of animal RNAs with regulatory potency. Nature 495, 333–338 (2013).

    Article  CAS  Google Scholar 

  68. Yang, Y. et al. Arginine methylation facilitates the recruitment of TOP3B to chromatin to prevent R loop accumulation. Mol. Cell 53, 484–497 (2014).

    Article  CAS  Google Scholar 

  69. Bhakar, A. L., Dolen, G. & Bear, M. F. The pathophysiology of fragile X (and what it teaches us about synapses). Annu. Rev. Neurosci. 35, 417–443 (2012).

    Article  CAS  Google Scholar 

  70. Yang, Y. et al. TDRD3 is an effector molecule for arginine-methylated histone marks. Mol. Cell 40, 1016–1023 (2010).

    Article  CAS  Google Scholar 

  71. Seki, T., Seki, M., Onodera, R., Katada, T. & Enomoto, T. Cloning of cDNA encoding a novel mouse DNA topoisomerase III (Topo IIIβ) possessing negatively supercoiled DNA relaxing activity, whose message is highly expressed in the testis. J. Biol. Chem. 273, 28553–28556 (1998).

    Article  CAS  Google Scholar 

  72. Aguilera, A. & Garcia-Muse, T. R loops: from transcription byproducts to threats to genome stability. Mol. Cell 46, 115–124 (2012).

    Article  CAS  Google Scholar 

  73. Skourti-Stathaki, K. & Proudfoot, N. J. A double-edged sword: R loops as threats to genome integrity and powerful regulators of gene expression. Genes Dev. 28, 1384–1396 (2014).

    Article  CAS  Google Scholar 

  74. Tuduri, S. et al. Topoisomerase I suppresses genomic instability by preventing interference between replication and transcription. Nat. Cell Biol. 11, 1315–1324 (2009).

    Article  CAS  Google Scholar 

  75. Rialdi, A. et al. Topoisomerase 1 inhibition suppresses inflammatory genes and protects from death by inflammation. Science 352, aad7993 (2016).

    Article  Google Scholar 

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Acknowledgements

The author thanks the US National Institutes of Health (NIH) (NS-37956, CA-21765), the Cancer Center Support Grant (CCSG) (P30 CA21765) and the American Lebanese and Syrian Associated Charities of St Jude Children's Research Hospital for financial support. Space constraints limited the number of primary research papers cited.

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  1. Department of Genetics, St Jude Children's Research Hospital, Memphis, 38105, Tennessee, USA

    Peter J. McKinnon

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McKinnon, P. Topoisomerases and the regulation of neural function. Nat Rev Neurosci 17, 673–679 (2016). https://doi.org/10.1038/nrn.2016.101

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