Topoisomerase I and Genome Stability: The Good and the Bad

  • Jang-Eun Cho
  • Sue Jinks-RobertsonEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1703)


Topoisomerase I (Top1) resolves torsional stress that accumulates during transcription, replication and chromatin remodeling by introducing a transient single-strand break in DNA. The cleavage activity of Top1 has opposing roles, either promoting or destabilizing genome integrity depending on the context. Resolution of transcription-associated negative supercoils, for example, prevents pairing of the nascent RNA with the DNA template (R-loops) as well as DNA secondary structure formation. Reduced Top1 levels thus enhance CAG repeat contraction, somatic hypermutation, and class switch recombination. Actively transcribed ribosomal DNA is also destabilized in the absence of Top1, reflecting the importance of Top1 in ensuring efficient transcription. In terms of promoting genome instability, an aborted Top1 catalytic cycle stimulates deletions at short tandem repeats and the enzyme’s transesterification activity supports illegitimate recombination. Finally, Top1 incision at ribonucleotides embedded in DNA generates deletions in tandem repeats, and induces gross chromosomal rearrangements and mitotic recombination.

Key words

Top1 Ribonucleotides R-loops Mutation 


  1. 1.
    Champoux JJ (2001) DNA topoisomerases: structure, function, and mechanism. Annu Rev Biochem 70:369–413. PubMedCrossRefGoogle Scholar
  2. 2.
    Wang JC (2002) Cellular roles of DNA topoisomerases: a molecular perspective. Nat Rev Mol Cell Biol 3(6):430–440. PubMedCrossRefGoogle Scholar
  3. 3.
    Pommier Y, Sun Y, Huang SN et al (2016) Roles of eukaryotic topoisomerases in transcription, replication and genomic stability. Nat Rev Mol Cell Biol 17(11):703–721. PubMedCrossRefGoogle Scholar
  4. 4.
    Liu LF, Wang JC (1987) Supercoiling of the DNA template during transcription. Proc Natl Acad Sci U S A 84(20):7024–7027PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Wu HY, Shyy SH, Wang JC et al (1988) Transcription generates positively and negatively supercoiled domains in the template. Cell 53(3):433–440PubMedCrossRefGoogle Scholar
  6. 6.
    Tanizawa A, Kohn KW, Pommier Y (1993) Induction of cleavage in topoisomerase I c-DNA by topoisomerase I enzymes from calf thymus and wheat germ in the presence and absence of camptothecin. Nucleic Acids Res 21(22):5157–5166PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Been MD, Burgess RR, Champoux JJ (1984) Nucleotide sequence preference at rat liver and wheat germ type 1 DNA topoisomerase breakage sites in duplex SV40 DNA. Nucleic Acids Res 12(7):3097–3114PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Shuman S, Prescott J (1990) Specific DNA cleavage and binding by vaccinia virus DNA topoisomerase I. J Biol Chem 265(29):17826–17836PubMedGoogle Scholar
  9. 9.
    Pourquier P, Ueng LM, Kohlhagen G et al (1997) Effects of uracil incorporation, DNA mismatches, and abasic sites on cleavage and religation activities of mammalian topoisomerase I. J Biol Chem 272(12):7792–7796PubMedCrossRefGoogle Scholar
  10. 10.
    Pommier Y, Barcelo JM, Rao VA et al (2006) Repair of topoisomerase I-mediated DNA damage. Prog Nucleic Acid Res Mol Biol 81:179–229. PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Schultz MC, Brill SJ, Ju Q et al (1992) Topoisomerases and yeast rRNA transcription: negative supercoiling stimulates initiation and topoisomerase activity is required for elongation. Genes Dev 6(7):1332–1341PubMedCrossRefGoogle Scholar
  12. 12.
    Fernandez X, Diaz-Ingelmo O, Martinez-Garcia B et al (2014) Chromatin regulates DNA torsional energy via topoisomerase II-mediated relaxation of positive supercoils. EMBO J 33(13):1492–1501.  10.15252/embj.201488091 PubMedPubMedCentralGoogle Scholar
  13. 13.
    Salceda J, Fernandez X, Roca J (2006) Topoisomerase II, not topoisomerase I, is the proficient relaxase of nucleosomal DNA. EMBO J 25(11):2575–2583. PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    French SL, Sikes ML, Hontz RD et al (2011) Distinguishing the roles of topoisomerases I and II in relief of transcription-induced torsional stress in yeast rRNA genes. Mol Cell Biol 31(3):482–494. PubMedCrossRefGoogle Scholar
  15. 15.
    Staker BL, Hjerrild K, Feese MD et al (2002) The mechanism of topoisomerase I poisoning by a camptothecin analog. Proc Natl Acad Sci U S A 99(24):15387–15392. PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Tomicic MT, Kaina B (2013) Topoisomerase degradation, DSB repair, p53 and IAPs in cancer cell resistance to camptothecin-like topoisomerase I inhibitors. Biochim Biophys Acta 1835(1):11–27. PubMedGoogle Scholar
  17. 17.
    Colley WC, van der Merwe M, Vance JR et al (2004) Substitution of conserved residues within the active site alters the cleavage religation equilibrium of DNA topoisomerase I. J Biol Chem 279(52):54069–54078. PubMedCrossRefGoogle Scholar
  18. 18.
    Andersen SL, Sloan RS, Petes TD et al (2015) Genome-destabilizing effects associated with Top1 loss or accumulation of Top1 cleavage complexes in yeast. PLoS Genet 11(4):e1005098. PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Sloan RS (2016) Topoisomerase 1 (Top1)-associated genome instability in yeast: effects of persistent cleavage complexes or increased Top1 levels. Dissertation, Duke UniversityGoogle Scholar
  20. 20.
    Husain I, Mohler JL, Seigler HF et al (1994) Elevation of topoisomerase I messenger RNA, protein, and catalytic activity in human tumors: demonstration of tumor-type specificity and implications for cancer chemotherapy. Cancer Res 54(2):539–546PubMedGoogle Scholar
  21. 21.
    Pfister TD, Reinhold WC, Agama K et al (2009) Topoisomerase I levels in the NCI-60 cancer cell line panel determined by validated ELISA and microarray analysis and correlation with indenoisoquinoline sensitivity. Mol Cancer Ther 8(7):1878–1884. PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Shamanna RA, Lu H, Croteau DL et al (2016) Camptothecin targets WRN protein: mechanism and relevance in clinical breast cancer. Oncotarget 7(12):13269–13284.  10.18632/oncotarget.7906 PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Koster DA, Palle K, Bot ES et al (2007) Antitumour drugs impede DNA uncoiling by topoisomerase I. Nature 448(7150):213–217. PubMedCrossRefGoogle Scholar
  24. 24.
    Ray Chaudhuri A, Hashimoto Y, Herrador R et al (2012) Topoisomerase I poisoning results in PARP-mediated replication fork reversal. Nat Struct Mol Biol 19(4):417–423. PubMedCrossRefGoogle Scholar
  25. 25.
    Yang SW, Burgin AB Jr, Huizenga BN et al (1996) A eukaryotic enzyme that can disjoin dead-end covalent complexes between DNA and type I topoisomerases. Proc Natl Acad Sci U S A 93(21):11534–11539PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Debethune L, Kohlhagen G, Grandas A et al (2002) Processing of nucleopeptides mimicking the topoisomerase I-DNA covalent complex by tyrosyl-DNA phosphodiesterase. Nucleic Acids Res 30(5):1198–1204PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Stingele J, Schwarz MS, Bloemeke N et al (2014) A DNA-dependent protease involved in DNA-protein crosslink repair. Cell 158(2):327–338. PubMedCrossRefGoogle Scholar
  28. 28.
    Balakirev MY, Mullally JE, Favier A et al (2015) Wss1 metalloprotease partners with Cdc48/Doa1 in processing genotoxic SUMO conjugates. elife 4.
  29. 29.
    Vance JR, Wilson TE (2001) Uncoupling of 3′-phosphatase and 5′-kinase functions in budding yeast. Characterization of Saccharomyces cerevisiae DNA 3′-phosphatase (TPP1). J Biol Chem 276(18):15073–15081. PubMedCrossRefGoogle Scholar
  30. 30.
    Vance JR, Wilson TE (2001) Repair of DNA strand breaks by the overlapping functions of lesion-specific and non-lesion-specific DNA 3′ phosphatases. Mol Cell Biol 21(21):7191–7198. PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Weinfeld M, Mani RS, Abdou I et al (2011) Tidying up loose ends: the role of polynucleotide kinase/phosphatase in DNA strand break repair. Trends Biochem Sci 36(5):262–271. PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Xu Y, Her C (2015) Inhibition of topoisomerase (DNA) I (TOP1): DNA damage repair and anticancer therapy. Biomol Ther 5(3):1652–1670. Google Scholar
  33. 33.
    Durand-Dubief M, Persson J, Norman U et al (2010) Topoisomerase I regulates open chromatin and controls gene expression in vivo. EMBO J 29(13):2126–2134. PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Marinello J, Chillemi G, Bueno S et al (2013) Antisense transcripts enhanced by camptothecin at divergent CpG-island promoters associated with bursts of topoisomerase I-DNA cleavage complex and R-loop formation. Nucleic Acids Res 41(22):10110–10123. PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Puc J, Kozbial P, Li W et al (2015) Ligand-dependent enhancer activation regulated by topoisomerase-I activity. Cell 160(3):367–380. PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Marinello J, Bertoncini S, Aloisi I et al (2016) Dynamic effects of topoisomerase I inhibition on R-loops and short transcripts at active promoters. PLoS One 11(1):e0147053. PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Rosenberg M, Fan AX, Lin IJ et al (2013) Cell-cycle specific association of transcription factors and RNA polymerase II with the human beta-globin gene locus. J Cell Biochem 114(9):1997–2006. PubMedCrossRefGoogle Scholar
  38. 38.
    Baranello L, Wojtowicz D, Cui K et al (2016) RNA polymerase II regulates topoisomerase 1 activity to favor efficient transcription. Cell 165(2):357–371. PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Phatnani HP, Greenleaf AL (2004) Identifying phosphoCTD-associating proteins. Methods Mol Biol 257:17–28. PubMedGoogle Scholar
  40. 40.
    Wu J, Phatnani HP, Hsieh TS et al (2010) The phosphoCTD-interacting domain of topoisomerase I. Biochem Biophys Res Commun 397(1):117–119. PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Husain A, Begum NA, Taniguchi T et al (2016) Chromatin remodeller SMARCA4 recruits topoisomerase 1 and suppresses transcription-associated genomic instability. Nat Commun 7:10549. PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Zylka MJ, Simon JM, Philpot BD (2015) Gene length matters in neurons. Neuron 86(2):353–355. PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    King IF, Yandava CN, Mabb AM et al (2013) Topoisomerases facilitate transcription of long genes linked to autism. Nature 501(7465):58–62. PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Mabb AM, Simon JM, King IF et al (2016) Topoisomerase 1 regulates gene expression in neurons through cleavage complex-dependent and -independent mechanisms. PLoS One 11(5):e0156439. PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Solier S, Ryan MC, Martin SE et al (2013) Transcription poisoning by topoisomerase I is controlled by gene length, splice sites, and miR-142-3p. Cancer Res 73(15):4830–4839. PubMedCrossRefGoogle Scholar
  46. 46.
    Chan YA, Aristizabal MJ, Lu PY et al (2014) Genome-wide profiling of yeast DNA:RNA hybrid prone sites with DRIP-Chip. PLoS Genet 10(4):e1004288. PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Wahba L, Amon JD, Koshland D et al (2011) RNase H and multiple RNA biogenesis factors cooperate to prevent RNA:DNA hybrids from generating genome instability. Mol Cell 44(6):978–988. PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Wahba L, Costantino L, Tan FJ et al (2016) S1-DRIP-seq identifies high expression and polyA tracts as major contributors to R-loop formation. Genes Dev 30(11):1327–1338. PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Rossi F, Labourier E, Forne T et al (1996) Specific phosphorylation of SR proteins by mammalian DNA topoisomerase I. Nature 381(6577):80–82. PubMedCrossRefGoogle Scholar
  50. 50.
    Labourier E, Rossi F, Gallouzi IE et al (1998) Interaction between the N-terminal domain of human DNA topoisomerase I and the arginine-serine domain of its substrate determines phosphorylation of SF2/ASF splicing factor. Nucleic Acids Res 26(12):2955–2962PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Soret J, Gabut M, Dupon C et al (2003) Altered serine/arginine-rich protein phosphorylation and exonic enhancer-dependent splicing in mammalian cells lacking topoisomerase I. Cancer Res 63(23):8203–8211PubMedGoogle Scholar
  52. 52.
    Malanga M, Czubaty A, Girstun A et al (2008) Poly(ADP-ribose) binds to the splicing factor ASF/SF2 and regulates its phosphorylation by DNA topoisomerase I. J Biol Chem 283(29):19991–19998. PubMedCrossRefGoogle Scholar
  53. 53.
    Huertas P, Aguilera A (2003) Cotranscriptionally formed DNA:RNA hybrids mediate transcription elongation impairment and transcription-associated recombination. Mol Cell 12(3):711–721PubMedCrossRefGoogle Scholar
  54. 54.
    Strasser K, Masuda S, Mason P et al (2002) TREX is a conserved complex coupling transcription with messenger RNA export. Nature 417(6886):304–308. PubMedCrossRefGoogle Scholar
  55. 55.
    Luna R, Rondon AG, Aguilera A (2012) New clues to understand the role of THO and other functionally related factors in mRNP biogenesis. Biochim Biophys Acta 1819(6):514–520. PubMedCrossRefGoogle Scholar
  56. 56.
    Gowrishankar J, Harinarayanan R (2004) Why is transcription coupled to translation in bacteria? Mol Microbiol 54(3):598–603. PubMedCrossRefGoogle Scholar
  57. 57.
    Leela JK, Syeda AH, Anupama K et al (2013) Rho-dependent transcription termination is essential to prevent excessive genome-wide R-loops in Escherichia coli. Proc Natl Acad Sci U S A 110(1):258–263. PubMedCrossRefGoogle Scholar
  58. 58.
    El Hage A, French SL, Beyer AL et al (2010) Loss of topoisomerase I leads to R-loop-mediated transcriptional blocks during ribosomal RNA synthesis. Genes Dev 24(14):1546–1558. PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Gan W, Guan Z, Liu J et al (2011) R-loop-mediated genomic instability is caused by impairment of replication fork progression. Genes Dev 25(19):2041–2056. PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Wellinger RE, Prado F, Aguilera A (2006) Replication fork progression is impaired by transcription in hyperrecombinant yeast cells lacking a functional THO complex. Mol Cell Biol 26(8):3327–3334. PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Zeman MK, Cimprich KA (2014) Causes and consequences of replication stress. Nat Cell Biol 16(1):2–9. PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Cerritelli SM, Crouch RJ (2009) Ribonuclease H: the enzymes in eukaryotes. FEBS J 276(6):1494–1505. PubMedCrossRefGoogle Scholar
  63. 63.
    Mischo HE, Gomez-Gonzalez B, Grzechnik P et al (2011) Yeast Sen1 helicase protects the genome from transcription-associated instability. Mol Cell 41(1):21–32. PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Skourti-Stathaki K, Proudfoot NJ, Gromak N (2011) Human senataxin resolves RNA/DNA hybrids formed at transcriptional pause sites to promote Xrn2-dependent termination. Mol Cell 42(6):794–805. PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Li X, Manley JL (2005) Inactivation of the SR protein splicing factor ASF/SF2 results in genomic instability. Cell 122(3):365–378. PubMedCrossRefGoogle Scholar
  66. 66.
    Aguilera A, Garcia-Muse T (2012) R loops: from transcription byproducts to threats to genome stability. Mol Cell 46(2):115–124. PubMedCrossRefGoogle Scholar
  67. 67.
    Skourti-Stathaki K, Proudfoot NJ (2014) A double-edged sword: R loops as threats to genome integrity and powerful regulators of gene expression. Genes Dev 28(13):1384–1396. PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Hamperl S, Cimprich KA (2014) The contribution of co-transcriptional RNA:DNA hybrid structures to DNA damage and genome instability. DNA Repair 19:84–94. PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Sollier J, Cimprich KA (2015) Breaking bad: R-loops and genome integrity. Trends Cell Biol 25(9):514–522. PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Tuduri S, Crabbe L, Conti C et al (2009) Topoisomerase I suppresses genomic instability by preventing interference between replication and transcription. Nat Cell Biol 11(11):1315–1324. PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Ribeyre C, Zellweger R, Chauvin M et al (2016) Nascent DNA proteomics reveals a chromatin remodeler required for topoisomerase I loading at replication forks. Cell Rep 15(2):300–309. PubMedCrossRefGoogle Scholar
  72. 72.
    Christman MF, Dietrich FS, Fink GR (1988) Mitotic recombination in the rDNA of S. cerevisiae is suppressed by the combined action of DNA topoisomerases I and II. Cell 55(3):413–425PubMedCrossRefGoogle Scholar
  73. 73.
    Houseley J, Kotovic K, El Hage A et al (2007) Trf4 targets ncRNAs from telomeric and rDNA spacer regions and functions in rDNA copy number control. EMBO J 26(24):4996–5006. PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Krawczyk C, Dion V, Schar P et al (2014) Reversible Top1 cleavage complexes are stabilized strand-specifically at the ribosomal replication fork barrier and contribute to ribosomal DNA stability. Nucleic Acids Res 42(8):4985–4995. PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Trigueros S, Roca J (2002) Failure to relax negative supercoiling of DNA is a primary cause of mitotic hyper-recombination in topoisomerase-deficient yeast cells. J Biol Chem 277(40):37207–37211. PubMedCrossRefGoogle Scholar
  76. 76.
    Tornaletti S, Park-Snyder S, Hanawalt PC (2008) G4-forming sequences in the non-transcribed DNA strand pose blocks to T7 RNA polymerase and mammalian RNA polymerase II. J Biol Chem 283(19):12756–12762. PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Lopes J, Piazza A, Bermejo R et al (2011) G-quadruplex-induced instability during leading-strand replication. EMBO J 30(19):4033–4046. PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    London TB, Barber LJ, Mosedale G et al (2008) FANCJ is a structure-specific DNA helicase associated with the maintenance of genomic G/C tracts. J Biol Chem 283(52):36132–36139. PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Paeschke K, Capra JA, Zakian VA (2011) DNA replication through G-quadruplex motifs is promoted by the Saccharomyces cerevisiae Pif1 DNA helicase. Cell 145(5):678–691. PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Kim N, Jinks-Robertson S (2011) Guanine repeat-containing sequences confer transcription-dependent instability in an orientation-specific manner in yeast. DNA Repair 10(9):953–960. PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Yadav P, Harcy V, Argueso JL et al (2014) Topoisomerase I plays a critical role in suppressing genome instability at a highly transcribed G-quadruplex-forming sequence. PLoS Genet 10(12):e1004839. PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Yadav P, Owiti N, Kim N (2016) The role of topoisomerase I in suppressing genome instability associated with a highly transcribed guanine-rich sequence is not restricted to preventing RNA:DNA hybrid accumulation. Nucleic Acids Res 44(2):718–729. PubMedCrossRefGoogle Scholar
  83. 83.
    Arimondo PB, Riou JF, Mergny JL et al (2000) Interaction of human DNA topoisomerase I with G-quartet structures. Nucleic Acids Res 28(24):4832–4838PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Marchand C, Pourquier P, Laco GS et al (2002) Interaction of human nuclear topoisomerase I with guanosine quartet-forming and guanosine-rich single-stranded DNA and RNA oligonucleotides. J Biol Chem 277(11):8906–8911. PubMedCrossRefGoogle Scholar
  85. 85.
    Shuai L, Deng M, Zhang D et al (2010) Quadruplex-duplex motifs as new topoisomerase I inhibitors. Nucleosides Nucleotides Nucleic Acids 29(11):841–853. PubMedCrossRefGoogle Scholar
  86. 86.
    Gazumyan A, Bothmer A, Klein IA et al (2012) Activation-induced cytidine deaminase in antibody diversification and chromosome translocation. Adv Cancer Res 113:167–190. PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Matthews AJ, Zheng S, DiMenna LJ et al (2014) Regulation of immunoglobulin class-switch recombination: choreography of noncoding transcription, targeted DNA deamination, and long-range DNA repair. Adv Immunol 122:1–57. PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Hwang JK, Alt FW, Yeap LS (2015) Related mechanisms of antibody somatic hypermutation and class switch recombination. Microbiol Spectr 3(1):Mdna3-0037-2014. PubMedGoogle Scholar
  89. 89.
    Senavirathne G, Bertram JG, Jaszczur M et al (2015) Activation-induced deoxycytidine deaminase (AID) co-transcriptional scanning at single-molecule resolution. Nat Commun 6:10209. PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Huang FT, Yu K, Balter BB et al (2007) Sequence dependence of chromosomal R-loops at the immunoglobulin heavy-chain Smu class switch region. Mol Cell Biol 27(16):5921–5932. PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Ruiz JF, Gomez-Gonzalez B, Aguilera A (2011) AID induces double-strand breaks at immunoglobulin switch regions and c-MYC causing chromosomal translocations in yeast THO mutants. PLoS Genet 7(2):e1002009. PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Kobayashi M, Aida M, Nagaoka H et al (2009) AID-induced decrease in topoisomerase 1 induces DNA structural alteration and DNA cleavage for class switch recombination. Proc Natl Acad Sci U S A 106(52):22375–22380. PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Kobayashi M, Sabouri Z, Sabouri S et al (2011) Decrease in topoisomerase I is responsible for activation-induced cytidine deaminase (AID)-dependent somatic hypermutation. Proc Natl Acad Sci U S A 108(48):19305–19310. PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Ronai D, Iglesias-Ussel MD, Fan M et al (2007) Detection of chromatin-associated single-stranded DNA in regions targeted for somatic hypermutation. J Exp Med 204(1):181–190. PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Maul RW, Saribasak H, Cao Z et al (2015) Topoisomerase I deficiency causes RNA polymerase II accumulation and increases AID abundance in immunoglobulin variable genes. DNA Repair 30:46–52. PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Gatchel JR, Zoghbi HY (2005) Diseases of unstable repeat expansion: mechanisms and common principles. Nat Rev Genet 6(10):743–755. PubMedCrossRefGoogle Scholar
  97. 97.
    La Spada AR, Taylor JP (2010) Repeat expansion disease: progress and puzzles in disease pathogenesis. Nat Rev Genet 11(4):247–258. PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Wojciechowska M, Krzyzosiak WJ (2011) CAG repeat RNA as an auxiliary toxic agent in polyglutamine disorders. RNA Biol 8(4):565–571. PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Hubert L Jr, Lin Y, Dion V et al (2011) Topoisomerase 1 and single-strand break repair modulate transcription-induced CAG repeat contraction in human cells. Mol Cell Biol 31(15):3105–3112. PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Caldecott KW (2008) Single-strand break repair and genetic disease. Nat Rev Genet 9(8):619–631. PubMedGoogle Scholar
  101. 101.
    Takahashi T, Burguiere-Slezak G, Van der Kemp PA et al (2011) Topoisomerase 1 provokes the formation of short deletions in repeated sequences upon high transcription in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A 108(2):692–697. PubMedCrossRefGoogle Scholar
  102. 102.
    Lippert MJ, Kim N, Cho JE et al (2011) Role for topoisomerase 1 in transcription-associated mutagenesis in yeast. Proc Natl Acad Sci U S A 108(2):698–703. PubMedCrossRefGoogle Scholar
  103. 103.
    Nick McElhinny SA, Watts BE, Kumar D et al (2010) Abundant ribonucleotide incorporation into DNA by yeast replicative polymerases. Proc Natl Acad Sci U S A 107(11):4949–4954. PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Nick McElhinny SA, Kumar D, Clark AB et al (2010) Genome instability due to ribonucleotide incorporation into DNA. Nat Chem Biol 6(10):774–781. PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Lujan SA, Williams JS, Clausen AR et al (2013) Ribonucleotides are signals for mismatch repair of leading-strand replication errors. Mol Cell 50(3):437–443. PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Williams JS, Clausen AR, Lujan SA et al (2015) Evidence that processing of ribonucleotides in DNA by topoisomerase 1 is leading-strand specific. Nat Struct Mol Biol 22(4):291–297. PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Sparks JL, Chon H, Cerritelli SM et al (2012) RNase H2-initiated ribonucleotide excision repair. Mol Cell 47(6):980–986. PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Kim N, Huang SN, Williams JS et al (2011) Mutagenic processing of ribonucleotides in DNA by yeast topoisomerase I. Science 332(6037):1561–1564. PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Clark AB, Lujan SA, Kissling GE et al (2011) Mismatch repair-independent tandem repeat sequence instability resulting from ribonucleotide incorporation by DNA polymerase ε. DNA Repair 10(5):476–482. PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Potenski CJ, Niu H, Sung P et al (2014) Avoidance of ribonucleotide-induced mutations by RNase H2 and Srs2-Exo1 mechanisms. Nature 511(7508):251–254. PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Niu H, Potenski CJ, Epshtein A et al (2016) Roles of DNA helicases and Exo1 in the avoidance of mutations induced by Top1-mediated cleavage at ribonucleotides in DNA. Cell Cycle 15(3):331–336. PubMedCrossRefGoogle Scholar
  112. 112.
    Williams JS, Smith DJ, Marjavaara L et al (2013) Topoisomerase 1-mediated removal of ribonucleotides from nascent leading-strand DNA. Mol Cell 49(5):1010–1015. PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Sekiguchi J, Shuman S (1997) Site-specific ribonuclease activity of eukaryotic DNA topoisomerase I. Mol Cell 1(1):89–97PubMedCrossRefGoogle Scholar
  114. 114.
    Cho JE, Kim N, Li YC et al (2013) Two distinct mechanisms of topoisomerase 1-dependent mutagenesis in yeast. DNA Repair 12(3):205–211. PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Sparks JL, Burgers PM (2015) Error-free and mutagenic processing of topoisomerase 1-provoked damage at genomic ribonucleotides. EMBO J 34(9):1259–1269.  10.15252/embj.201490868 PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Huang SY, Ghosh S, Pommier Y (2015) Topoisomerase I alone is sufficient to produce short DNA deletions and can also reverse nicks at ribonucleotide sites. J Biol Chem 290(22):14068–14076. PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Cho JE, Huang SN, Burgers PM et al (2016) Parallel analysis of ribonucleotide-dependent deletions produced by yeast Top1 in vitro and in vivo. Nucleic Acids Res 44(16):7714–7721. PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Cho JE, Kim N, Jinks-Robertson S (2015) Topoisomerase 1-dependent deletions initiated by incision at ribonucleotides are biased to the non-transcribed strand of a highly activated reporter. Nucleic Acids Res 43(19):9306–9313. PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Cho JE, Jinks-Robertson S (2016) Ribonucleotides and transcription-associated mutagenesis in yeast. J Mol Biol.
  120. 120.
    Stewart L, Redinbo MR, Qiu X et al (1998) A model for the mechanism of human topoisomerase I. Science 279(5356):1534–1541PubMedCrossRefGoogle Scholar
  121. 121.
    Wu J, Liu LF (1997) Processing of topoisomerase I cleavable complexes into DNA damage by transcription. Nucleic Acids Res 25(21):4181–4186PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Conover HN, Lujan SA, Chapman MJ et al (2015) Stimulation of chromosomal rearrangements by ribonucleotides. Genetics 201(3):951–961. PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Epshtein A, Potenski CJ, Klein HL (2016) Increased spontaneous recombination in RNase H2-deficient cells arises from multiple contiguous rNMPs and not from single rNMP residues incorporated by DNA polymerase epsilon. Microb Cell 3(6):248–254PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Allen-Soltero S, Martinez SL, Putnam CD et al (2014) A Saccharomyces cerevisiae RNase H2 interaction network functions to suppress genome instability. Mol Cell Biol 34(8):1521–1534. PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Mankouri HW, Ngo HP, Hickson ID (2009) Esc2 and Sgs1 act in functionally distinct branches of the homologous recombination repair pathway in Saccharomyces cerevisiae. Mol Biol Cell 20(6):1683–1694. PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Ii M, Ii T, Mironova LI et al (2011) Epistasis analysis between homologous recombination genes in Saccharomyces cerevisiae identifies multiple repair pathways for Sgs1, Mus81-Mms4 and RNase H2. Mutat Res 714(1–2):33–43. PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Chon H, Sparks JL, Rychlik M et al (2013) RNase H2 roles in genome integrity revealed by unlinking its activities. Nucleic Acids Res 41(5):3130–3143. PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Llorente B, Smith CE, Symington LS (2008) Break-induced replication: what is it and what is it for? Cell Cycle 7(7):859–864. PubMedCrossRefGoogle Scholar
  129. 129.
    O’Connell K, Jinks-Robertson S, Petes TD (2015) Elevated genome-wide instability in yeast mutants lacking RNase H activity. Genetics 201(3):963–975. PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Shuman S, Turner J (1993) Site-specific interaction of vaccinia virus topoisomerase I with base and sugar moieties in duplex DNA. J Biol Chem 268(25):18943–18950PubMedGoogle Scholar
  131. 131.
    Been MD, Champoux JJ (1984) Breakage of single-stranded DNA by eukaryotic type 1 topoisomerase occurs only at regions with the potential for base-pairing. J Mol Biol 180(3):515–531PubMedCrossRefGoogle Scholar
  132. 132.
    Waters CA, Strande NT, Wyatt DW et al (2014) Nonhomologous end joining: a good solution for bad ends. DNA Repair 17:39–51. PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Christiansen K, Svejstrup AB, Andersen AH et al (1993) Eukaryotic topoisomerase I-mediated cleavage requires bipartite DNA interaction. Cleavage of DNA substrates containing strand interruptions implicates a role for topoisomerase I in illegitimate recombination. J Biol Chem 268(13):9690–9701PubMedGoogle Scholar
  134. 134.
    Henningfeld KA, Hecht SM (1995) A model for topoisomerase I-mediated insertions and deletions with duplex DNA substrates containing branches, nicks, and gaps. Biochemistry 34(18):6120–6129PubMedCrossRefGoogle Scholar
  135. 135.
    Bullock P, Champoux JJ, Botchan M (1985) Association of crossover points with topoisomerase I cleavage sites: a model for nonhomologous recombination. Science 230(4728):954–958PubMedCrossRefGoogle Scholar
  136. 136.
    Kovac MB, Kovacova M, Bachraty H et al (2015) High-resolution breakpoint analysis provides evidence for the sequence-directed nature of genome rearrangements in hereditary disorders. Hum Mutat 36(2):250–259. PubMedCrossRefGoogle Scholar
  137. 137.
    Zhu J, Schiestl RH (1996) Topoisomerase I involvement in illegitimate recombination in Saccharomyces cerevisiae. Mol Cell Biol 16:1805–1812PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Zhu J, Schiestl RH (2004) Human topoisomerase I mediates illegitimate recombination leading to DNA insertion into the ribosomal DNA locus in Saccharomyces cerevisiae. Mol Gen Genomics 271(3):347–358. CrossRefGoogle Scholar
  139. 139.
    Pommier Y, Jenkins J, Kohlhagen G et al (1995) DNA recombinase activity of eukaryotic DNA topoisomerase I; effects of camptothecin and other inhibitors. Mutat Res 337(2):135–145PubMedCrossRefGoogle Scholar
  140. 140.
    Behrendt R, Roers A (2014) Mouse models for Aicardi-Goutières syndrome provide clues to the molecular pathogenesis of systemic autoimmunity. Clin Exp Immunol 175(1):9–16. PubMedCrossRefGoogle Scholar
  141. 141.
    Lim YW, Sanz LA, Xu X et al (2015) Genome-wide DNA hypomethylation and RNA:DNA hybrid accumulation in Aicardi-Goutières syndrome. elife 4.
  142. 142.
    Li M, Pokharel S, Wang JT et al (2015) RECQ5-dependent SUMOylation of DNA topoisomerase I prevents transcription-associated genome instability. Nat Commun 6:6720. PubMedCrossRefGoogle Scholar
  143. 143.
    Li M, Liu Y (2016) Topoisomerase I in human disease pathogenesis and treatments. Genomics Proteomics Bioinformatics 14(3):166–171. PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2018

Authors and Affiliations

  1. 1.Department of Molecular Genetics and MicrobiologyDuke University Medical CenterDurhamUSA

Personalised recommendations