Mol. DNA Polymerase: Structure, Types and Functions ISSN 1471-003X (print). (2001), Residues within the N-terminal domain of human topoisomerase I play a direct role in relaxation, Interthal H, Quigley PM, Hol WG, Champoux JJ (2004), The role of lysine 532 in the catalytic mechanism of human topoisomerase I, Yeast DNA topoisomerase II. Hansen, T. B. et al. (2008), Bone marrow and tumor cell colony-forming units and human tumor xenograft efficacy of noncamptothecin and camptothecin topoisomerase I inhibitors, Zhou W, Dai Z, Chen Y, Wang H, Yuan Z (2012), High-Dimensional descriptor selection and computational QSAR modeling for antitumor activity of ARC-111 analogues based on Support Vector Regression (SVR), Indolocarbazole natural products: occurrence, biosynthesis, and biological activity, Urasaki Y, Laco G, Takebayashi Y, Bailly C, Kohlhagen G, Pommier Y (2001), Use of camptothecin-resistant mammalian cell lines to evaluate the role of topoisomerase I in the antiproliferative activity of the indolocarbazole, NB-506, and its topoisomerase I binding site, The indenoisoquinoline noncamptothecin topoisomerase I inhibitors: update and perspectives, {"type":"clinical-trial","attrs":{"text":"NCT01051635","term_id":"NCT01051635"}}, Kurtzberg LS, Roth S, Krumbholz R, Crawford J, Bormann C, Dunham S, et al. To relieve strain ahead of the replication fork, topoisomerase breaks a covalent bond in the sugar-phosphate backbone of one of the two parental strands. Nature 495, 333338 (2013). The interactions formed between the topoisomerase and each drug may explain the drugs specificity toward Top 2-mediated DNA breaks. Nature 495, 384388 (2013). (1991), Inhibition of intracellular topoisomerase II by antitumor bis(2,6-dioxopiperazine) derivatives: mode of cell growth inhibition distinct from that of cleavable complex-forming type inhibitors, Roca J, Ishida R, Berger JM, Andoh T, Wang JC (1994), Antitumor bisdioxopiperazines inhibit yeast DNA topoisomerase II by trapping the enzyme in the form of a closed protein clamp, Analysis of a core domain in Drosophila DNA topoisomerase II. What is the function of Primase in DNA replication? 28 February 2022, Nature Neuroscience Easily accessible podophyllotoxin is used in the synthesis of etoposide (Etopophos, VePesid, VP-16) and teniposide (Vumon, VM-26) [296]. To overcome these limitations, non-camptothecin hTop 1 inhibitors have been developed and investigated [177180]. What is the function of a topoisomerase in DNA replication? Open 3, 172184 (2014). Therefore, inactivation of a type II topoisomerase can be achieved by restricting the nucleotide-dependent structural changes or inhibiting ATPase activity. (2013), Novel hydroxyl tricyclics (e.g., GSK966587) as potent inhibitors of bacterial type IIA topoisomerases, Miles TJ, Hennessy AJ, Bax B, Brooks G, Brown BS, Brown P, et al. Sci. Proc. As described in the previous section, fluoroquinolones interact with the conserved amino acid residues in the WHD domain of the GyrA/ParC subunit. 16, 144154 (2015). Blocking the transportation of the T-segment by the F plasmid-encoded protein CcdB represents another mechanism of gyrase inhibition [238,239]. A structural feature unique to the DNA gate is that, to perform strand breakage and religation reactions, the catalytic tyrosine of one subunit must team up with the Mg2+ presented by the Toprim domain of the opposing subunit [44,123,124,127129]. (2012), Mitochondrial topoisomerase I is critical for mitochondrial integrity and cellular energy metabolism, Khiati S, Baechler SA, Factor VM, Zhang H, Huang SY, Dalla Rosa I, et al. Molecular mechanism of DNA replication (article) | Khan Academy (1995), Novel antitumor indolocarbazole compound 6-N-formylamino-12,13-dihydro-1,11- dihydroxy-13-(beta-D-glucopyranosyl)-5H-indolo[2,3-a]pyrrolo[3,4- c]carbazole-5,7(6H)-dione (NB-506): induction of topoisomerase I-mediated DNA cleavage and mechanisms of cell line-selective cytotoxicity, Arakawa H, Iguchi T, Morita M, Yoshinari T, Kojiri K, Suda H, et al. Both replicated circular and linear DNA chromosomes are separated by type II topoisomerases. In human somatic cells proliferation potential is strictly limited and senescence follows approximat It was the first hTop 1 inhibitor approved for oral administration [168,169]. TDRD3 is an effector molecule for arginine-methylated histone marks. McKinnon, P. J. As a result, this small molecule is capable of inhibiting the supercoiling activity of gyrase by preventing gyrase from binding to DNA, rather than by inhibiting the ATPase activity of gyrase [232]. What is the function of topoisomerase relieving strain in the DNA ahead of the replication fork? Why is DNA gyrase topoisomerase necessary for replication? With gate closure and opening being controlled by ATP, the gate appears to act as a nucleotide-operated protein clamp suitable for T-segment capture. As was the case with topoisomerase-fluoroquinolone-DNA ternary complexes [217], topoisomerase-NBTI-DNA ternary complexes could arrest replication fork progression in vitro [31]. DNA gyrase: structure and function sharing sensitive information, make sure youre on a federal Keeney, S. Spo11 and the formation of DNA double-strand breaks in meiosis. (2013), Catalytic inhibitors of topoisomerase II differently modulate the toxicity of anthracyclines in cardiac and cancer cells, Larsen AK, Escargueil AE, Skladanowski A (2003), Catalytic topoisomerase II inhibitors in cancer therapy, Lu J, Patel S, Sharma N, Soisson SM, Kishii R, Takei M, et al. Rev. Nucleic Acids Res. 3), indicating that these two distinct classes of NBTIs target the same conformational state of the enzyme-DNA complex and may act synergistically [218]. Ann Oncol. The main function of DNA polymerase: DNA polymerases are the molecular precursors of DNA (deoxyribonucleic acid). DNA topoisomerases, especially type IIA topoisomerases, are proven therapeutic targets of anticancer and antibacterial drugs. Rev. It is not clear, however, if the effect of camptothecins on mTop 1 contribute to the anticancer activities of these drugs. HHS Vulnerability Disclosure, Help It is used to treat ALL, AML, chronic myelogenous leukemia (CML), and Kaposis sarcoma [314317]. A major incentive for developing new compounds against bacterial type IIA topoisomerases is to overcome the growing resistance to quinolone antibacterial agents. Camptothecin analogues in the treatment of non-small cell lung cancer. It has been demonstrated that the E-ring exists in equilibrium between lactone (closed-ring) and carboxylate (open-ring) forms under physiological condition [138]. Irinotecan and topotecan are derived from camptothecins, cytotoxic compounds which were initially isolated from the bark of the Chinese tree, Camptotheca acuminata. PLoS Genet. The strand breakage site-specific drug binding physically blocks the religation reaction [136,137]. Telomerase: structure, functions, and activity regulation Sawada S, Matsuoka S, Nagata H, Furuta T, Yokokura T, Miyasaka T (1991), Synthesis and antitumor activity of 20(S)-camptothecin derivatives: A-ring modified and 7,10-disubstituted camptothecins, Synthesis of CPT-11 (irinotecan hydrochloride trihydrate), Satoh T, Hosokawa M, Atsumi R, Suzuki W, Hakusui H, Nagai E (1994), Metabolic activation of CPT-11, 7-ethyl-10-[4-(1-piperidino)-1- piperidino]carbonyloxycamptothecin, a novel antitumor agent, by carboxylesterase, Rivory LP, Bowles MR, Robert J, Pond SM (1996), Conversion of irinotecan (CPT-11) to its active metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), by human liver carboxylesterase, Irinotecan (CPT-11): Recent Developments and Future Directions - Colorectal Cancer and Beyond, Brangi M, Litman T, Ciotti M, Nishiyama K, Kohlhagen G, Takimoto C, et al. El-Khamisy, S. F. et al. As a result, they alter the linking number in steps of one [17]. Each subtype of topoisomerase is structurally and functionally conserved and forms a protein family [17]. Top 2 is required for DNA replication and chromosome segregation [7780], and its expression is significantly elevated in proliferating and cancer cells [8184]. (Textbook of pharmacology and therapeutics; mentions that etoposide and teniposide [VP-16 and VP-26] are semisynthetic derivatives of podophyllotoxin, an extract from the mandrake plant or mayapple [Podophyllum peltatum], which bind to topoisomerase 2 and DNA and preempt resealing of DNA breaks that occur during DNA replication). Before Bermejo, R., Lai, M. S. & Foiani, M. Preventing replication stress to maintain genome stability: resolving conflicts between replication and transcription. Chen, S. H., Chan, N. L. & Hsieh, T. S. New mechanistic and functional insights into DNA topoisomerases. Nat. (2000), Simocyclinones, novel cytostatic angucyclinone antibiotics produced by Streptomyces antibioticus T 6040. An official website of the United States government. The key difference between helicase and topoisomerase is that helicase is an enzyme that separates two complementary strands of DNA by breaking hydrogen bonds between the bases of two strands while topoisomerase is an enzyme that removes positive and negative supercoils formed during the unwinding process of DNA by . Irinotecan and topotecan are two camptothecin derivatives currently in use in the United States and are used as adjunctive therapies for advanced colorectal, ovarian and small cell lung cancer. (2013), Mycobacterium fluoroquinolone resistance protein B, a novel small GTPase, is involved in the regulation of DNA gyrase and drug resistance, YacG from Escherichia coli is a specific endogenous inhibitor of DNA gyrase, Vos SM, Lyubimov AY, Hershey DM, Schoeffler AJ, Sengupta S, Nagaraja V, et al. In addition, they can intercalate into DNA [326] and may influence the functions of various proteins besides hTop 2 [327329]. Proc. Madabhushi, R. et al. First, it binds to the parental DNA ahead of the replication fork. Structural studies indicated that CcdB binds to the large cavity enclosed by the two GyrA subunits by interacting with cavity-facing residues from the C-gate region of gyrase (Fig. Natl Acad. Topoisomerases as anticancer targets - PubMed Structural modeling further suggested that CcdB cannot be accommodated in the cavity if the cleavage complex adopts the closed conformation, a state essential for resealing the cleaved DNA [240]. Recent advances in the field have suggested a possibility of designing isoform-specific human topoisomerase II poisons, which may be developed as safer anticancer drugs. In addition, it is also required for development and the survival of some neural cells [8587]. The Top 1-catalyzed relaxation reaction is also impaired [141] because the stacking interactions between the bound drug and 5-base pair about the scissile phosphate would increase the threshold energy for the downstream DNA to rotate. Nitiss, J. L. DNA topoisomerase II and its growing repertoire of biological functions. MfpA and Qnr adopt a quadrilateral -helix fold, with overall dimensions and distribution of negatively charged groups on their protein surface markedly resembling features of B-form DNA [222225]. 8600 Rockville Pike To obtain Open Access Topoisomerases catalyze and guide the unknotting or unlinking of DNA by creating transient breaks in the DNA using a conserved tyrosine as the catalytic residue. The DNA upstream of the single-strand break is tightly bound through several proteinDNA interactions between the core of Top 1 and DNA, primarily to the phosphate backbone of the DNA, and is thus unable to rotate.