Molecular mechanisms of topoisomerase 2 DNA–protein crosslink resolution

  • Amanda A. Riccio
  • Matthew J. Schellenberg
  • R. Scott WilliamsEmail author


The compaction of DNA and the continuous action of DNA transactions, including transcription and DNA replication, create complex DNA topologies that require Type IIA Topoisomerases, which resolve DNA topological strain and control genome dynamics. The human TOP2 enzymes catalyze their reactions via formation of a reversible covalent enzyme DNA–protein crosslink, the TOP2 cleavage complex (TOP2cc). Spurious interactions of TOP2 with DNA damage, environmental toxicants and chemotherapeutic “poisons” perturbs the TOP2 reaction cycle, leading to an accumulation of DNA–protein crosslinks, and ultimately, genomic instability and cell death. Emerging evidence shows that TOP2-DNA protein crosslink (DPC) repair entails multiple strand break repair activities, such as removal of the poisoned TOP2 protein and rejoining of the DNA ends through homologous recombination (HR) or non-homologous end joining (NHEJ). Herein, we discuss the molecular mechanisms of TOP2-DPC resolution, with specific emphasis on the recently uncovered ZATTZnf451-licensed TDP2-catalyzed TOP2-DPC reversal mechanism.


DNA strand breaks Topoisomerase 2 Structural biology Tyrosyl DNA phosphodiesterase 2 Tdp2 ZATT ZNF451 TOP2 Chemotherapeutics 



This research was supported by the intramural research program of the US National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS) Grant 1Z01ES102765 to R.S.W.


  1. 1.
    Witz G, Stasiak A (2009) DNA supercoiling and its role in DNA decatenation and unknotting. Nucleic Acids Res 38(7):2119–2133PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    King IF et al (2013) Topoisomerases facilitate transcription of long genes linked to autism. Nature 501(7465):58–62PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Tammaro M, Barr P, Ricci B, Yan H (2013) Replication-dependent and transcription-dependent mechanisms of DNA double-strand break induction by the topoisomerase 2-targeting drug etoposide. PLoS One 8(11):e79202PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Zhang L, Wang S, Yin S, Hong S, Kim KP, Kleckner N (2014) Topoisomerase II mediates meiotic crossover interference. Nature 511(7511):551–556PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Nitiss JL (2009) DNA topoisomerase II and its growing repertoire of biological functions. Nat Rev Cancer 9(5):327–337PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Schoeffler AJ, Berger JM (2008) DNA topoisomerases: harnessing and constraining energy to govern chromosome topology. Q Rev Biophys 41(1):41–101PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Nitiss JL, Soans E, Berk J, Seth A, Mishina M, Nitiss KC (2012) Repair of topoisomerase II-mediated DNA damage: fixing dna damage arising from a protein covalently trapped on DNA. In: Pommier Y (ed) DNA topoisomerases and cancer. Cancer drug discovery and development. Springer, New York, NYGoogle Scholar
  8. 8.
    Wang JC (2002) Cellular roles of DNA topoisomerases: a molecular perspective. Nat Rev Mol Cell Biol 3:430PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Chen GL, Yang L, Rowe TC, Halligan BD, Tewey KM, Liu LF (1984) Nonintercalative antitumor drugs interfere with the breakage-reunion reaction of mammalian DNA topoisomerase II. J Biol Chem 259:13560–13566PubMedPubMedCentralGoogle Scholar
  10. 10.
    Ashour ME, Atteya R, El-Khamisy SF (2015) Topoisomerase-mediated chromosomal break repair: an emerging player in many games. Nat Rev Cancer 15(3):137–151PubMedCrossRefGoogle Scholar
  11. 11.
    McClendon AK, Osheroff N (2007) DNA topoisomerase II, genotoxicity, and cancer. Mutat Res 623(1–2):83–97PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Drake FH et al (1987) Purification of topoisomerase II from amsacrine-resistant P388 leukemia cells. Evidence for two forms of the enzyme. J Biol Chem 262:16739–16747PubMedGoogle Scholar
  13. 13.
    Drake FH, Hofmann GA, Bartus HF, Mattern MR, Crooke ST, Mirabelli CK (1989) Biochemical and pharmacological properties of p170 and p180 forms of topoisomerase II. Biochemistry 28:8154–8160PubMedCrossRefGoogle Scholar
  14. 14.
    Mirabelli CK, Crooke ST, Mao Ji (1992) Topoisomerase Ila and topoisomerase 11/3 genes: characterization and mapping to human chromosomes 17 and 3, respectively. Cancer Res 52(14):3831–3837Google Scholar
  15. 15.
    Tsai-Pflugfelder M et al (1988) Cloning and sequencing of cDNA encoding human DNA topoisomerase II and localization of the gene to chromosome region 17q21-22. Proc Natl Acad Sci USA 85:7177–7181PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Capranico G, Tinelli S, Austin CA, Fisher ML, Zunino F (1992) Different patterns of gene expression of topoisomerase II isoforms in differentiated tissues during murine development. Biochim Biophys Acta - Gene Struct Expr 1132(1):43–48CrossRefGoogle Scholar
  17. 17.
    Watanabe M, Tsutsui K, Tsutsui K, Inoue Y (1994) Differential expressions of the topoisomerase IIα and IIβ mRNAs in developing rat brain. Neurosci Res 19(1):51–57PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Schmidt BH, Osheroff N, Berger JM (2012) Structure of a topoisomerase II-DNA-nucleotide complex reveals a new control mechanism for ATPase activity. Nat Struct Mol Biol 19(11):1147–1154PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Ryu H et al (2015) SUMOylation of the C-terminal domain of DNA topoisomerase IIα regulates the centromeric localization of Claspin. Cell Cycle 14(17):2777–2784PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Kozuki T et al (2017) Roles of the C-terminal domains of topoisomerase IIα’ and topoisomerase IIβ in regulation of the decatenation checkpoint. Nucleic Acids Res 45(10):5995–6010PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Dickey JS, Osheroff N (2005) Impact of the C-terminal domain of topoisomerase IIα on the DNA cleavage activity of the human enzyme. Biochemistry 44(34):11546–11554PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Austin CA, Sng JH, Patel S, Fisher LM (1993) Novel HeLa topoisomerase II is the IIβ isoform: complete coding sequence and homology with other type II topoisomerases. BBA - Gene Struct Expr 1172(3):283–291CrossRefGoogle Scholar
  23. 23.
    Chen S-F et al (2018) Structural insights into the gating of DNA passage by the topoisomerase II DNA-gate. Nat Commun 9(1):3085PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Wendorff TJ, Schmidt BH, Heslop P, Austin CA, Berger JM (2012) The structure of DNA-bound human topoisomerase II alpha: conformational mechanisms for coordinating inter-subunit interactions with DNA cleavage. J Mol Biol 424(3–4):109–124PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Wu CC et al (2011) Structural basis of type II topoisomerase inhibition by the anticancer drug etoposide. Science (80–) 333(6041):459–462CrossRefGoogle Scholar
  26. 26.
    Nitiss JL (2009) Targeting DNA topoisomerase II in cancer chemotherapy. Nat Rev Cancer 9(5):338–350PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Pommier Y (2013) Drugging topoisomerases: lessons and challenges. ACS Chem Biol 8(1):82–95PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Karimi Goftar M, Alizadeh Rayeni N, Rasouli S (2014) Topoisomerase inhibitors and types of them. Int J Adv Biol Biomed Res 2(8):2431–2436Google Scholar
  29. 29.
    Deweese JE, Osheroff N (2009) The DNA cleavage reaction of topoisomerase II: wolf in sheep’s clothing. Nucleic Acids Res 37(3):738–748PubMedCrossRefGoogle Scholar
  30. 30.
    Williams JS, Kunkel TA (2014) Ribonucleotides in DNA: origins, repair and consequences. DNA Repair (Amst) 19:27–37PubMedCentralCrossRefPubMedGoogle Scholar
  31. 31.
    Andres SN, Schellenberg MJ, Wallace BD, Tumbale P, Williams RS (2015) Recognition and repair of chemically heterogeneous structures at DNA ends. Environ Mol Mutagen 56(1):1–21PubMedCrossRefGoogle Scholar
  32. 32.
    Wallace BD, Williams RS (2014) Ribonucleotide triggered DNA damage and RNA-DNA damage responses. RNA Biol 11(11):1340–1346PubMedCrossRefGoogle Scholar
  33. 33.
    Gao R et al (2014) Proteolytic degradation of topoisomerase II (Top2) enables the processing of Top2 DNA and Top2 RNA covalent complexes by tyrosyl-DNA-phosphodiesterase 2 (TDP2). J Biol Chem 289(26):17960–17969PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Wang Y, Knudsen BR, Bjergbæk L, Westergaard O, Andersen AH (1999) Stimulated activity of human topoisomerases IIα and IIβ on RNA-containing substrates. J Biol Chem 274:22839–22846PubMedCrossRefGoogle Scholar
  35. 35.
    Cline SD, Jones WR, Stone MP, Osheroff N (1999) DNA abasic lesions in a different light: solution structure of an endogenous topoisomerase II poison. Biochemistry 38(47):15500–15507PubMedCrossRefGoogle Scholar
  36. 36.
    Khan QA et al (2003) Position-specific trapping of topoisomerase II by benzo[a]pyrene diol epoxide adducts: implications for interactions with intercalating anticancer agents. Proc Natl Acad Sci 100(21):12498–12503PubMedCrossRefGoogle Scholar
  37. 37.
    Sabourin M, Osheroff N (2000) Sensitivity of human type II topoisomerases to DNA damage: stimulation of enzyme-mediated DNA cleavage by abasic, oxidized and alkylated lesions. Nucleic Acids Res 28(9):1947–1954PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Kingma PS, Osheroff N (1997) Apurinic sites are position-specific topoisomerase II poisons. J Biol Chem 272(2):1148–1155PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Hande KR (1998) Etoposide: four decades of development of a topoisomerase II inhibitor. Eur J Cancer 34(10):1514–1521PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Baldwin EL, Osheroff N (2005) Etoposide, topoisomerase II and cancer. Curr Med Chem Anticancer Agents 5(4):363–372PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Wu C-C, Li Y-C, Wang Y-R, Li T-K, Chan N-L (2013) On the structural basis and design guidelines for type II topoisomerase-targeting anticancer drugs. Nucleic Acids Res 41(22):10630–10640PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Zagnoli-Vieira G et al (2018) Confirming TDP2 mutation in spinocerebellar ataxia autosomal recessive 23 (SCAR23). Neurol Genet 4(4):e262PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Ciaccio C et al (2019) Consolidating the role of TDP2 mutations in recessive spinocerebellar ataxia associated with pediatric onset drug resistant epilepsy and intellectual disability (SCAR23). The Cerebellum 18(5):972–975PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Gómez-Herreros F et al (2014) TDP2 protects transcription from abortive topoisomerase activity and is required for normal neural function. Nat Genet 46:516PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Gómez-Herreros F et al (2017) TDP2 suppresses chromosomal translocations induced by DNA topoisomerase II during gene transcription. Nat Commun 8(1):233PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Felix CA, Kolaris CP, Osheroff N (2006) Topoisomerase II and the etiology of chromosomal translocations. DNA Repair (Amst) 5(9):1093–1108CrossRefGoogle Scholar
  47. 47.
    Strick R, Strissel PL, Borgers S, Smith SL, Rowley JD (2000) Dietary bioflavonoids induce cleavage in the MLL gene and may contribute to infant leukemia. Proc Natl Acad Sci USA 97(9):4790–4795PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Cowell IG et al (2012) Model for MLL translocations in therapy-related leukemia involving topoisomerase IIβ-mediated DNA strand breaks and gene proximity. Proc Natl Acad Sci USA 109(23):8989–8994PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Strissel PL, Strick R, Rowley JD, Zeleznik-Le NJ (1998) An in vivo topoisomerase II cleavage site and a DNase I hypersensitive site colocalize near exon 9 in the MLL breakpoint cluster region. Blood 92(10):3793–3803PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Cortes Ledesma F, El Khamisy SF, Zuma MC, Osborn K, Caldecott KW (2009) A human 5′-tyrosyl DNA phosphodiesterase that repairs topoisomerase-mediated DNA damage. Nature 461(7264):674–678PubMedCrossRefGoogle Scholar
  51. 51.
    Schellenberg MJ et al (2017) ZATT (ZNF451)-mediated resolution of topoisomerase 2 DNA-protein cross-links. Science 357(6358):1412–1416PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Rao T et al (2016) Novel TDP2-ubiquitin interactions and their importance for the repair of topoisomerase II-mediated DNA damage. Nucleic Acids Res 44(21):10201–10215PubMedPubMedCentralGoogle Scholar
  53. 53.
    Schellenberg MJ et al (2016) Reversal of DNA damage induced topoisomerase 2 DNA-protein crosslinks by Tdp2. Nucleic Acids Res 44(8):3829–3844PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Shi K et al (2012) Structural basis for recognition of 5′-phosphotyrosine adducts by TDP2. Nat Struct Mol Biol 19(12):1372–1377PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Schellenberg MJ, Appel CD, Adhikari S, Robertson PD, Ramsden DA, Williams RS (2012) Mechanism of repair of 5′-topoisomerase II-DNA adducts by mammalian tyrosyl-DNA phosphodiesterase 2. Nat Struct Mol Biol 19(12):1363–1371PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Gao R, Huang SN, Marchand C, Pommier Y (2012) Biochemical characterization of human tyrosyl-DNA phosphodiesterase 2 (TDP2/TTRAP): a Mg(2+)/Mn(2+)-dependent phosphodiesterase specific for the repair of topoisomerase cleavage complexes. J Biol Chem 287(36):30842–30852PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Mao Y, Desai SD, Ting CY, Hwang J, Liu LF (2001) 26 S proteasome-mediated degradation of topoisomerase II cleavable complexes. J Biol Chem 276(44):40652–40658PubMedCrossRefGoogle Scholar
  58. 58.
    Lee KC, Swan RL, Sondka Z, Padget K, Cowell IG, Austin CA (2018) Effect of TDP2 on the level of TOP2-DNA complexes and SUMOylated TOP2-DNA complexes. Int J Mol Sci 19(7):2056PubMedCentralCrossRefPubMedGoogle Scholar
  59. 59.
    Zhang A et al (2006) A protease pathway for the repair of topoisomerase II-DNA covalent complexes. J Biol Chem 281(47):35997–36003PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Stingele J, Jentsch S (2015) DNA-protein crosslink repair. Nat Rev Mol Cell Biol 16(8):455–460PubMedCrossRefGoogle Scholar
  61. 61.
    Stingele J, Schwarz MS, Bloemeke N, Wolf PG, Jentsch S (2014) A DNA-dependent protease involved in DNA-protein crosslink repair. Cell 158(2):327–338PubMedCrossRefGoogle Scholar
  62. 62.
    Tang X, Cao J, Zhang L, Huang Y, Zhang Q, Rong YS (2017) Maternal Haploid, a Metalloprotease enriched at the largest satellite repeat and essential for genome integrity in Drosophila embryos. Genetics 206(4):1829–1839PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Duxin JP, Dewar JM, Yardimci H, Walter JC (2014) Repair of a DNA-protein crosslink by replication-coupled proteolysis. Cell 159(2):349–357CrossRefGoogle Scholar
  64. 64.
    Deshpande RA, Lee JH, Arora S, Paull TT (2016) Nbs1 converts the human Mre11/Rad50 nuclease complex into an endo/exonuclease machine specific for protein-DNA adducts. Mol Cell 64(3):593–606PubMedCrossRefGoogle Scholar
  65. 65.
    Gómez-Herreros F et al (2013) TDP2-dependent non-homologous end-joining protects against topoisomerase II-induced DNA breaks and genome instability in cells and in vivo. PLoS Genet 9(3):e1003226PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Williams GJ, Hammel M, Radhakrishnan SK, Ramsden D, Lees-Miller SP, Tainer JA (2014) Structural insights into NHEJ: building up an integrated picture of the dynamic DSB repair super complex, one component and interaction at a time. DNA Repair (Amst) 17:110–120CrossRefGoogle Scholar
  67. 67.
    Azuma Y, Arnaoutov A, Anan T, Dasso M (2005) PIASy mediates SUMO-2 conjugation of Topoisomerase-II on mitotic chromosomes. EMBO J 24(12):2172–2182PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Li H, Wang Y, Liu X (2008) Plk1-dependent phosphorylation regulates functions of DNA topoisomerase IIα in cell cycle progression. J Biol Chem 283(10):6209–6221PubMedCrossRefGoogle Scholar
  69. 69.
    Jackson SP, Durocher D (2013) Regulation of DNA damage responses by ubiquitin and SUMO. Mol Cell 49(5):795–807PubMedCrossRefGoogle Scholar
  70. 70.
    Pichler A, Fatouros C, Lee H, Eisenhardt N (2017) SUMO conjugation—a mechanistic view. Biomol Concepts 8(1):13–36CrossRefGoogle Scholar
  71. 71.
    Kawale AS, Povirk LF (2018) Tyrosyl–DNA phosphodiesterases: rescuing the genome from the risks of relaxation. Nucleic Acids Res 46(2):520–537PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Bian K et al (2016) ERK3 regulates TDP2-mediated DNA damage response and chemoresistance in lung cancer cells. Oncotarget 7(6):6665–6675PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Cappadocia L, Pichler A, Lima CD (2015) Structural basis for catalytic activation by the human ZNF451 SUMO E3 ligase. Nat Struct Mol Biol 22(12):968–975PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Koidl S, Eisenhardt N, Fatouros C, Droescher M, Chaugule VK, Pichler A (2016) The SUMO2/3 specific E3 ligase ZNF451-1 regulates PML stability. Int J Biochem Cell Biol 79:478–487PubMedCrossRefGoogle Scholar
  75. 75.
    Abascal F, Tress ML, Valencia A (2015) Alternative splicing and co-option of transposable elements: the case of TMPO/LAP2α and ZNF451 in mammals. Bioinformatics 31(14):2257–2261PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Karvonen U, Jääskeläinen T, Rytinki M, Kaikkonen S, Palvimo JJ (2008) ZNF451 is a novel PML body- and SUMO-associated transcriptional coregulator. J Mol Biol 382(3):585–600PubMedCrossRefGoogle Scholar
  77. 77.
    Matelska D, Steczkiewicz K, Ginalski K (2017) Comprehensive classification of the PIN domain-like superfamily. Nucleic Acids Res 45(12):6995–7020PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Fedotova AA, Bonchuk AN, Mogila VA, Georgiev PG (2017) C2H2 zinc finger proteins: the largest but poorly explored family of higher eukaryotic transcription factors. Acta Naturae 9(2):47–58PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Fradet-Turcotte A et al (2013) 53BP1 is a reader of the DNA-damage-induced H2A Lys 15 ubiquitin mark. Nature 499(7456):50–54PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Hendriks IA, Lyon D, Young C, Jensen LJ, Vertegaal ACO, Nielsen ML (2017) Site-specific mapping of the human SUMO proteome reveals co-modification with phosphorylation. Nat Struct Mol Biol 24:325PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Eisenhardt N et al (2015) A new vertebrate SUMO enzyme family reveals insights into SUMO-chain assembly. Nat Struct Mol Biol 22(12):959–967PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Hendriks IA, D’Souza RCJ, Yang B, Verlaan-de Vries M, Mann M, Vertegaal ACO (2014) Uncovering global SUMOylation signaling networks in a site-specific manner. Nat Struct Mol Biol 21(10):927–936PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Hendriks IA, Treffers LW, Verlaan-de Vries M, Olsen JV, Vertegaal ACO (2015) SUMO-2 orchestrates chromatin modifiers in response to DNA damage. Cell Rep. CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Ho C-W, Chen H-T, Hwang J (2011) UBC9 autosumoylation negatively regulates sumoylation of septins in Saccharomyces cerevisiae. J Biol Chem 286(24):21826–21834PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Yoshida MM, Azuma Y (2016) Mechanisms behind topoisomerase II SUMOylation in chromosome segregation. Cell Cycle 15(23):3151–3152PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Mao Y, Desai SD, Liu LF (2000) SUMO-1 conjugation to human DNA topoisomerase II isozymes. J Biol Chem 275(34):26066–26073PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Agostinho M et al (2008) Conjugation of human topoisomerase 2α with small ubiquitin-like modifiers 2/3 in response to topoisomerase inhibitors: cell cycle stage and chromosome domain specificity. Cancer Res 68(7):2409–2418PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    Ryu H, Furuta M, Kirkpatrick D, Gygi SP, Azuma Y (2010) PIASy-dependent SUMOylation regulates DNA topoisomerase IIalpha activity. J Cell Biol 191(4):783–794PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Radhakrishnan SK, Jette N, Lees-Miller SP (2014) Non-homologous end joining: emerging themes and unanswered questions. DNA Repair (Amst) 17:2–8CrossRefGoogle Scholar
  90. 90.
    Kont YS et al (2016) Depletion of tyrosyl DNA phosphodiesterase 2 activity enhances etoposide-mediated double-strand break formation and cell killing. DNA Repair (Amst) 43:38–47CrossRefGoogle Scholar
  91. 91.
    Do PM et al (2012) Mutant p53 cooperates with ETS2 to promote etoposide resistance. Genes Dev 26(8):830–845PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Li C, Fan S, Owonikoko TK, Khuri FR, Sun S-Y, Li R (2011) Oncogenic role of EAPII in lung cancer development and its activation of the MAPK–ERK pathway. Oncogene 30(35):3802–3812PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Hornyak P et al (2016) Mode of action of DNA-competitive small molecule inhibitors of tyrosyl DNA phosphodiesterase 2. Biochem J 473(13):1869–1879PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Kossmann BR et al (2016) Discovery of selective inhibitors of tyrosyl-DNA phosphodiesterase 2 by targeting the enzyme DNA-binding cleft. Bioorg Med Chem Lett 26(14):3232–3236PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Yu LM et al (2018) Synthesis and structure-activity relationship of furoquinolinediones as inhibitors of Tyrosyl-DNA phosphodiesterase 2 (TDP2). Eur J Med Chem 151:777–796PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Komulainen E, Pennicott L, Le Grand D, Caldecott KW (2019) Deazaflavin inhibitors of TDP2 with cellular activity can affect etoposide influx and/or efflux. ACS Chem Biol 14(6):1110–1114PubMedCrossRefGoogle Scholar

Copyright information

© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply  2019

Authors and Affiliations

  • Amanda A. Riccio
    • 1
  • Matthew J. Schellenberg
    • 1
  • R. Scott Williams
    • 1
    Email author
  1. 1.Department of Health and Human Services, Genome Integrity and Structural Biology LaboratoryNational Institute of Environmental Health Sciences, US National Institutes of HealthResearch Triangle ParkUSA

Personalised recommendations