[en] The widely used quinolone antibiotics act by trapping prokaryotic type IIA topoisomerases, resulting in irreversible topoisomerase cleavage complexes (TOPcc). Whereas the excision repair pathways of TOPcc in eukaryotes have been extensively studied, it is not known whether equivalent repair pathways for prokaryotic TOPcc exist. By combining genetic, biochemical, and molecular biology approaches, we demonstrate that exonuclease VII (ExoVII) excises quinolone-induced trapped DNA gyrase, an essential prokaryotic type IIA topoisomerase. We show that ExoVII repairs trapped type IIA TOPcc and that ExoVII displays tyrosyl nuclease activity for the tyrosyl-DNA linkage on the 5'-DNA overhangs corresponding to trapped type IIA TOPcc. ExoVII-deficient bacteria fail to remove trapped DNA gyrase, consistent with their hypersensitivity to quinolones. We also identify an ExoVII inhibitor that synergizes with the antimicrobial activity of quinolones, including in quinolone-resistant bacterial strains, further demonstrating the functional importance of ExoVII for the repair of type IIA TOPcc.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Huang, Shar-Yin N ; Laboratory of Molecular Pharmacology, Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA. shar-yin.huang@nih.gov pommier@nih.gov.
Michaels, Stephanie A; Laboratory of Molecular Pharmacology, Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Mitchell, Brianna B; Laboratory of Molecular Pharmacology, Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Majdalani, Nadim ; Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Vanden Broeck, Arnaud ; Integrated Structural Biology Department, IGBMC, UMR7104 CNRS, U1258 Inserm, University of Strasbourg, Illkirch 67404, France.
Canela, Andres ; The Hakubi Center for Advanced Research, Radiation Biology Center, Graduate School of Biostudies, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Tse-Dinh, Yuk-Ching ; Department of Chemistry and Biochemistry, Biomolecular Sciences Institute, Florida International University, Miami, FL 33199, USA.
Lamour, Valerie ; Integrated Structural Biology Department, IGBMC, UMR7104 CNRS, U1258 Inserm, University of Strasbourg, Illkirch 67404, France.
Pommier, Yves ; Laboratory of Molecular Pharmacology, Developmental Therapeutics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA. shar-yin.huang@nih.gov pommier@nih.gov.
Language :
English
Title :
Exonuclease VII repairs quinolone-induced damage by resolving DNA gyrase cleavage complexes.
Publication date :
March 2021
Journal title :
Science Advances
eISSN :
2375-2548
Publisher :
American Association for the Advancement of Science (AAAS), Washington, Us dc
Volume :
7
Issue :
10
Peer reviewed :
Peer Reviewed verified by ORBi
Funding number :
Z01 BC006150/ImNIH/Intramural NIH HHS/United States
K. J. Aldred, T. R. Blower, R. J. Kerns, J. M. Berger, N. Osheroff, Fluoroquinolone interactions with Mycobacterium tuberculosis gyrase: Enhancing drug activity against wild-type and resistant gyrase. Proc. Natl. Acad. Sci. U.S.A. 113, E839–E846 (2016).
A. K. McClendon, N. Osheroff, DNA topoisomerase II, genotoxicity, and cancer. Mutat. Res. 623, 83–97 (2007).
V. Nagaraja, A. A. Godbole, S. R. Henderson, A. Maxwell, DNA topoisomerase I and DNA gyrase as targets for TB therapy. Drug Discov. Today 22, 510–518 (2017).
J. L. Nitiss, Targeting DNA topoisomerase II in cancer chemotherapy. Nat. Rev. Cancer 9, 338–350 (2009).
Y. Pommier, Drugging topoisomerases: Lessons and challenges. ACS Chem. Biol. 8, 82–95 (2012).
M. I. Andersson, A. P. MacGowan, Development of the quinolones. J. Antimicrob. Chemother. 51 (Suppl 1), 1–11 (2003).
J. F. Acar, F. W. Goldstein, Trends in bacterial resistance to fluoroquinolones. Clin. Infect. Dis. 24 (Suppl 1), S67–S73 (1997).
B. D. Bax, G. Murshudov, A. Maxwell, T. Germe, DNA topoisomerase inhibitors: Trapping a DNA-cleaving machine in motion. J. Mol. Biol. 431, 3427–3449 (2019).
Y. Pommier, C. Marchand, Interfacial inhibitors: Targeting macromolecular complexes. Nat. Rev. Drug Discov. 11, 25–36 (2011).
Y. Pommier, S. N. Huang, R. Gao, B. B. Das, J. Murai, C. Marchand, Tyrosyl-DNAphosphodiesterases (TDP1 and TDP2). DNA Repair 19, 114–129 (2014).
M. L. Henderson, K. N. Kreuzer, Functions that Protect Escherichia coli from Tightly Bound DNA-protein complexes created by mutant EcoRII Methyltransferase. PLOS ONE 10, e0128092 (2015).
C. Tamae, A. Liu, K. Kim, D. Sitz, J. Hong, E. Becket, A. Bui, P. Solaimani, K. P. Tran, H. Yang, J. H. Miller, Determination of antibiotic hypersensitivity among 4,000 single-gene-knockout mutants of Escherichia coli. J. Bacteriol. 190, 5981–5988 (2008).
J. W. Chase, C. C. Richardson, Exonuclease VII of Escherichia coli. Basic Life Sci. 5A, 225–234 (1975).
J. W. Chase, C. C. Richardson, Escherichia coli mutants deficient in exonuclease VII. J. Bacteriol. 129, 934–947 (1977).
P. Sharma, J. R. J. Haycocks, A. D. Middlemiss, R. A. Kettles, L. E. Sellars, V. Ricci, L. J. V. Piddock, D. C. Grainger, The multiple antibiotic resistance operon of enteric bacteria controls DNA repair and outer membrane integrity. Nat. Commun. 8, 1444 (2017).
R. J. Nichols, S. Sen, Y. J. Choo, P. Beltrao, M. Zietek, R. Chaba, S. Lee, K. M. Kazmierczak, K. J. Lee, A. Wong, M. Shales, S. Lovett, M. E. Winkler, N. J. Krogan, A. Typas, C. A. Gross, Phenotypic landscape of a bacterial cell. Cell 144, 143–156 (2011).
S. Bagel, V. Hullen, B. Wiedemann, P. Heisig, Impact of gyrA and parC mutations on quinolone resistance, doubling time, and supercoiling degree of Escherichia coli. Antimicrob. Agents Chemother. 43, 868–875 (1999).
B. C. L. van der Putten, D. Remondini, G. Pasquini, V. A. Janes, S. Matamoros, C. Schultsz, Quantifying the contribution of four resistance mechanisms to ciprofloxacin MIC in Escherichia coli: A systematic review. J. Antimicrob. Chemother. 74, 298–310 (2019).
B. D. Bax, P. F. Chan, D. S. Eggleston, A. Fosberry, D. R. Gentry, F. Gorrec, I. Giordano, M. M. Hann, A. Hennessy, M. Hibbs, J. Huang, E. Jones, J. Jones, K. K. Brown, C. J. Lewis, E. W. May, M. R. Saunders, O. Singh, C. E. Spitzfaden, C. Shen, A. Shillings, A. J. Theobald, A. Wohlkonig, N. D. Pearson, M. N. Gwynn, Type IIA topoisomerase inhibition by a new class of antibacterial agents. Nature 466, 935–940 (2010).
C. Marchand, M. Abdelmalak, J. Kankanala, S.-Y. Huang, E. Kiselev, K. Fesen, K. Kurahashi, H. Sasanuma, S. Takeda, H. Aihara, Z. Wang, Y. Pommier, Deazaflavin inhibitors of tyrosyl-DNA phosphodiesterase 2 (TDP2) specific for the human enzyme and active against cellular TDP2. ACS Chem. Biol. 11, 1925–1933 (2016).
M. Vestergaard, B. Leng, J. Haaber, M. S. Bojer, C. S. Vegge, H. Ingmer, Genome-wide identification of antimicrobial intrinsic resistance determinants in Staphylococcus aureus. Front. Microbiol. 7, 2018 (2016).
G. Narula, T. Annamalai, S. Aedo, B. Cheng, E. Sorokin, A. Wong, Y. C. Tse-Dinh, The strictly conserved Arg-321 residue in the active site of Escherichia coli topoisomerase I plays a critical role in DNA rejoining. J. Biol. Chem. 286, 18673–18680 (2011).
A. J. Schoeffler, J. M. Berger, Recent advances in understanding structure-function relationships in the type II topoisomerase mechanism. Biochem. Soc. Trans. 33, 1465–1470 (2005).
B. Cheng, S. Shukla, S. Vasunilashorn, S. Mukhopadhyay, Y.-C. Tse-Dinh, Bacterial cell killing mediated by topoisomerase I DNA cleavage activity. J. Biol. Chem. 280, 38489–38495 (2005).
J. C. Wang, DNA topoisomerases: Why so many? J. Biol. Chem. 266, 6659–6662 (1991).
J. W. Chase, C. C. Richardson, Exonuclease VII of Escherichia coli. Purification and propertiescoli. J. Biol. Chem. 249, 4545–4552 (1974).
T. Jain, B. J. Roper, A. Grove, A functional type I topoisomerase from Pseudomonas aeruginosa. BMC Mol. Biol. 10, 23 (2009).
B. O. Krogh, S. Shuman, A poxvirus-like type IB topoisomerase family in bacteria. Proc. Natl. Acad. Sci. U.S.A. 99, 1853–1858 (2002).
M. Ahmad, Y. Xue, S. K. Lee, J. L. Martindale, W. Shen, W. Li, S. Zou, M. Ciaramella, H. Debat, M. Nadal, F. Leng, H. Zhang, Q. Wang, G. E. Siaw, H. Niu, Y. Pommier, M. Gorospe, T. S. Hsieh, Y. C. Tse-Dinh, D. Xu, W. Wang, RNA topoisomerase is prevalent in all domains of life and associates with polyribosomes in animals. Nucleic Acids Res. 44, 6335–6349 (2016).
H. Wang, R. J. Di Gate, N. C. Seeman, An RNA topoisomerase. Proc. Natl. Acad. Sci. U.S.A. 93, 9477–9482 (1996).
A. Canela, Y. Maman, S. N. Huang, G. Wutz, W. Tang, G. Zagnoli-Vieira, E. Callen, N. Wong, A. Day, J. M. Peters, K. W. Caldecott, Y. Pommier, A. Nussenzweig, Topoisomerase II-induced chromosome breakage and translocation is determined by chromosome architecture and transcriptional activity. Mol. Cell 75, 252–266.e8 (2019).
S. Aedo, Y. C. Tse-Dinh, Isolation and quantitation of topoisomerase complexes accumulated on Escherichia coli chromosomal DNA. Antimicrob. Agents Chemother. 56, 5458–5464 (2012).
K. J. Aldred, A. Payne, O. Voegerl, A RADAR-based assay to isolate covalent DNA complexes in bacteria. Antibiotics 8, 17 (2019).
S. Aedo, Y. C. Tse-Dinh, SbcCD-mediated processing of covalent gyrase-DNA complex in Escherichia coli. Antimicrob. Agents Chemother. 57, 5116–5119 (2013).
E. J. Begg, R. A. Robson, D. A. Saunders, G. G. Graham, R. C. Buttimore, A. M. Neill, G. I. Town, The pharmacokinetics of oral fleroxacin and ciprofloxacin in plasma and sputum during acute and chronic dosing. Br. J. Clin. Pharmacol. 49, 32–38 (2000).
F. Cortes Ledesma, S. F. El Khamisy, M. C. Zuma, K. Osborn, K. W. Caldecott, A human 5’-tyrosyl DNA phosphodiesterase that repairs topoisomerase-mediated DNA damage. Nature 461, 674–678 (2009).
S.-W. Yang, A. B. Burgin, B. N. Huizenga, C. A. Robertson, K. C. Yao, H. A. Nash, A eukaryotic enzyme that can disjoin dead-end covalent complexes between DNA and type I topoisomerases. Proc. Natl. Acad. Sci. U.S.A. 93, 11534–11539 (1996).
S. Saha, Y. Sun, S. Huang, U. Jo, H. Zhang, Y. C. Tse-Dinh, Y. Pommier, Topoisomerase 3B (TOP3B) DNA and RNA cleavage complexes and pathway to repair TOP3B-linked RNA and DNA breaks. Cell Rep. 33, 108569 (2020).
H. Interthal, H. J. Chen, J. J. Champoux, Human Tdp1 cleaves a broad spectrum of substrates, including phosphoamide linkages. J. Biol. Chem. 280, 36518–36528 (2005).
R. Gao, M. J. Schellenberg, S.-Y. N. Huang, M. Abdelmalak, C. Marchand, K. C. Nitiss, J. L. Nitiss, R. S. Williams, Y. Pommier, 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, 17960–17969 (2014).
R. Gao, S. Y. Huang, C. Marchand, Y. Pommier, Biochemical characterization of human tyrosyl-DNA phosphodiesterase 2 (TDP2/TTRAP): A Mg2+/Mn2+-dependent phosphodiesterase specific for the repair of topoisomerase cleavage complexes. J. Biol. Chem. 287, 30842–30852 (2012).
K. Drlica, X. Zhao, DNA gyrase, topoisomerase IV, and the 4-quinolones. Microbiol. Mol. Biol. Rev. 61, 377–392 (1997).
J. Kankanala, C. Marchand, M. Abdelmalak, H. Aihara, Y. Pommier, Z. Wang, Isoquinoline-1,3-diones as selective inhibitors of tyrosyl DNA phosphodiesterase II (TDP2). J. Med. Chem. 59, 2734–2746 (2016).
K. Poleszak, K. H. Kaminska, S. Dunin-Horkawicz, A. Lupas, K. J. Skowronek, J. M. Bujnicki, Delineation of structural domains and identification of functionally important residues in DNA repair enzyme exonuclease VII. Nucleic Acids Res. 40, 8163–8174 (2012).
J. C. Wang, Cellular roles of DNA topoisomerases: A molecular perspective. Nat. Rev. Mol. Cell Biol. 3, 430–440 (2002).
M. Pieren, M. Tigges, Adjuvant strategies for potentiation of antibiotics to overcome antimicrobial resistance. Curr. Opin. Pharmacol. 12, 551–555 (2012).
E. Kiselev, A. Ravji, J. Kankanala, J. Xie, Z. Wang, Y. Pommier, Novel deazaflavin tyrosyl-DNA phosphodiesterase 2 (TDP2) inhibitors. DNA Repair 85, 102747 (2020).
K. Shi, K. Kurahashi, R. Gao, S. E. Tsutakawa, J. A. Tainer, Y. Pommier, H. Aihara, Structural basis for recognition of 5′-phosphotyrosine adducts by Tdp2. Nat. Struct. Mol. Biol. 19, 1372–1377 (2012).
M. J. Schellenberg, C. D. Appel, S. Adhikari, P. D. Robertson, D. A. Ramsden, R. S. Williams, Mechanism of repair of 5′-topoisomerase II-DNA adducts by mammalian tyrosyl-DNA phosphodiesterase 2. Nat. Struct. Mol. Biol. 19, 1363–1371 (2012).
J. H. Miller, A Short Course in Bacterial Genetics (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1992).
A. Vanden Broeck, C. Lotz, J. Ortiz, V. Lamour, Cryo-EM structure of the complete E. coli DNA gyrase nucleoprotein complex. Nat. Commun. 10, 4935 (2019).
