Anticancer drugs targeting TOP2 enzymes (Supplementary Box 1) are associated with long-term undesirable side effects including therapy-related acute myeloid leukaemia (t-AML)17,286,287. Nature 518, 409412 (2015). Biochim. [20] Transcription by RNA polymerase also generates positive supercoiling ahead of, and negative supercoiling behind, the transcriptional complex (Fig. Science 357, 14121416 (2017). This article reveals the role of TOP2-DPCs as a source of breast cancers in patients deficient in BRCA1. Holm, C., Goto, T., Wang, J. C. & Bolstein, D. DNA topoisomerase II is required at the time of mitosis in yeast. [47] However, dexrazoxane, which blocks ATP hydrolysis by topo II, is used to prevent cardiotoxicity associated with the anthracyclines. Commun. Zhang, H., Meng, L. H., Zimonjic, D. B., Popescu, N. C. & Pommier, Y. Thirteen-exon-motif signature for vertebrate nuclear and mitochondrial type IB topoisomerases. 25, 25752583 (2006). Cell. 6, 10191 (2015). 12, 5010 (2021). 40, e105393 (2021). Canela, A. et al. Telomere length heterogeneity in ALT cells is maintained by PML-dependent localization of the BTR complex to telomeres. Nat. Nature 442, 818822 (2006). DNA topoisomerases (or topoisomerases) are enzymes that catalyze changes in the topological state of DNA, interconverting relaxed and supercoiled forms, linked (catenated) and unlinked species, and knotted and unknotted DNA. Bjornsti, M. A. 5b), NHEJ is crucial for repair of TOP2-DPCs. The main differences between TOP2A and TOP2B are in the polypeptide sequence of their carboxy-terminal domains (CTDs) (Supplementary Fig. Its main effectors are Ku70Ku80 and DNA-dependent protein kinase (DNA-PK). Cellular roles of DNA topoisomerases: a molecular perspective These compounds work by interacting with their target (gyrase or topo IV) and DNA at the cleavage site to stabilize the DNA-protein covalent cleavage intermediate. Poly(ADP-ribose) polymerase and XPF-ERCC1 participate in distinct pathways for the repair of topoisomerase I-induced DNA damage in mammalian cells. [56][57][58] For the genes at which it occurs, the DNA double-stranded break induced by TOP2B is thought to be part of the process of regulation of gene expression. Hirabayashi, S. et al. Commun. Deiss, K. et al. Berti, M. et al. PubMedGoogle Scholar. Cell Res. 352, 15291538 (2005). Cell 49, 10101015 (2013). Recent analyses in human B cells show that more than 90% of TOP1-DPCs are removed during a 15-min repair time in wild type and TDP2/ cells, 70% in TDP1/ cells and only 40% in TDP1/TDP2/ cells253. & Pommier, Y. Topoisomerase I-mediated cleavage at unrepaired ribonucleotides generates DNA double-strand breaks. 14, 854864 (2017). 1c). Three forms of DNA are most prevalent in nature: circular, linear and supercoiled." Circular DNA is covalently closed and does not have any interruption between nucleotides. 1. eNeuro 4, ENEURO.0404-17.2017 (2017). Arnould, C. et al. Sci. Desai, S. D., Liu, L. F., Vazquez-Abad, D. & DArpa, P. Ubiquitin-dependent destruction of topoisomerase I is stimulated by the antitumor drug camptothecin. Google Scholar. Sci. Tang, Z. et al. The canonical pathway of ribonucleotide excision repair is primarily carried out by RNAse H2 (ref.146). Loop extrusion requires the ATPase activity and the translocation of cohesins, which stops upon cohesin encountering a CTCF protein bound to DNA in a convergent orientation98,99,100,101. Lin, Y. et al. Nucleic Acids Res. Mol. Madabhushi, R. et al. The ribonuclease activity of TOP1 has been linked with the Indel Signature 4 (ID4) in the Catalogue of Somatic Mutations in Cancer (COSMIC) database361, which consists of 25 base pair deletions. Interact. Dyson, S., Segura, J., Martinez-Garcia, B., Valdes, A. The removal of cohesin at prophase through the so-called prophase pathway is crucial for successful mitosis as condensins replace cohesins93. Chapman, J., Ng, Y. S. & Nicholls, T. J. & Baxter, J. Cohesin causes replicative DNA damage by trapping DNA topological stress. This work is a detailed review of SMC complexes. Spartan deficiency causes accumulation of topoisomerase 1 cleavage complexes and tumorigenesis. Pommier, Y., Jenkins, J., Kohlhagen, G. & Leteurtre, F. DNA recombinase activity of eukaryotic DNA topoisomerase I; effects of camptothecin and other inhibitors. Bidirectionalreplication and transcription of mtDNA represent model systems for DNA supercoiling, R-loops, G quadruplexes and decatenation. Differential and common DNA repair pathways for topoisomerase I- and II-targeted drugs in a genetic DT40 repair cell screen panel. Sci. Proc. (TADs). Lam, C. W., Yeung, W. L. & Law, C. Y. TOP1MT is not required for mtDNA transcription175,176,324 and for mouse development173,325, implying that other topoisomerase(s) relax Sc+ in mtDNA173. This excellent article reviews the discovery and biology of TOP2B. The exception among the type I topoisomerases, reverse gyrase, which contains a helicase domain (EC 3.6.4.12) and introduces positive supercoiling in an ATP-dependent manner. Hars, E. S., Lyu, Y. L., Lin, C.-P. & Liu, L. F. Role of apoptotic nuclease caspase-activated DNase in etoposide-induced treatment-related acute myelogenous leukemia. It is plausible, but not formally demonstrated, that the accumulation of Sc could be attenuated when transcription complexes follow each other in tandem, as the Sc generated by a transcription complex could be absorbed by (and facilitate the translocation of) the following transcription complex (Fig. USA 97, 18851890 (2000). Failure to separate these strands leads to cell death. Hasan, S. K. et al. Breast cancer accounts for about 35% of t-AML cases, presumably owing to the relative number of breast cancer cases and the age profile of the individuals, and prior haematological malignancies account for approximately 30% of t-AML cases288. Decatenation reactions are carried out by TOP2 enzymes1 (Fig. A critical role for the ubiquitin-conjugating enzyme Ubc13 in initiating homologous recombination. Proc. Science 287, 131134 (2000). Towards a therapy for Angelman syndrome by targeting a long non-coding RNA. Gothe, H. J. et al. Biol. Ahmad, M. et al. The potential role of DNA repair factors (including TDPs, ataxia telangiectasia mutated (ATM) and DNA-dependent protein kinase (DNA-PK)) in ligand-induced gene activation also remains to be elucidated. Biophys. [64][65] The pausing of RNA polymerase II at these sites and the controlled release of the pausing is thought to have a regulatory role in gene transcription. Rev. Development of autoimmunity in mice lacking DNA topoisomerase 3. DNA Repair. TOP1 converts them to SSBs (Fig. Shuman, S. Vaccinia DNA topoisomerase I promotes illegitimate recombination in Escherichia coli. Rev. The existence of topoisomerases is necessitated by the structure of the double helix. Studies with anticancer drugs that target TOPccs and with self-poisoning topoisomerases provide complementary approaches to elucidate the DNA damaging effects of trapped TOPccs and the repair pathways of and cellular responses to TOP1ccs31, TOP1MTccs202, TOP2ccs203,204 and TOP3Bccs2. Both the type IIA topoisomerases and the type IA topoisomerases TOP3A and TOP3B cleave nucleic acids by forming 5 DPCs with the help of magnesium positioning nucleic acids in their active site3,6 (Supplementary Fig. In the case of the archaeal enzyme, reverse gyrase, positive supercoiling of DNA is possible. Gyrase belongs to a class of enzymes known as topoisomerases that are involved in the control of topological transitions of DNA. The precise point or points during haematopoietic differentiation where progenitors can be transformed in this way is open to debate, but the window of opportunity is likely between multipotential progenitor cells and granulocytemacrophage progenitors290,291,292,293,294. 293, 1052410535 (2018). Kim, N. et al. 42, 44354449 (2014). 45, 45644576 (2017). Mechanism of generation of therapy related leukemia in response to anti-topoisomerase II agents. Cancer 16, 387398 (2016). They are also grateful to the three reviewers who provided multiple suggestions and careful corrections. J. Bacteriol. Libura, J., Slater, D. J., Felix, C. A. Meng, L. et al. 272, 77927796 (1997). Another unsolved question is the molecular mechanism(s) linking MRE11 with NHEJ to ensure the accurate repair of TOP2ccs, as NHEJ cannot accurately rejoin DSBs carrying the 3 overhangs generated by the endonucleolytic removal of TOP2 adducts. Aragon, L. The Smc5/6 complex: new and old functions of the enigmatic long-distance relative. Article 473, 169180 (2001). Cancer 9, 327337 (2009). Nat. Condensin also generates Sc+ in an ATP-dependent manner within those loops, which further contributes to chromosome compaction. Schalbetter, S. A., Mansoubi, S., Chambers, A. L., Downs, J. Lee, M. P., Brown, S. D., Chen, A. Mitochondrial topoisomerase I (Top1mt) is a novel limiting factor of doxorubicin cardiotoxicity. Earnshaw, W. C., Halligan, B., Cooke, C. A., Heck, M. M. & Liu, L. F. Topoisomerase II is a structural component of mitotic chromosome scaffolds. DNA topoisomerase II and its growing repertoire of biological - Nature Trans. It is therefore, a type IB topoisomerase, see the record on Topoisomerases Champoux (2001). Shuman, S. Polynucleotide ligase activity of eukaryotic topoisomerase I. Mol. Cell Biol. 287, 3084230852 (2012). Because of the potential danger of topoisomerases, it is likely that their activity is controlled and restricted to proper sites of action. (In supercoiling the DNA molecule coils up like a telephone cord, which shortens the molecule.) Roles of eukaryotic topoisomerases in transcription, replication and 14, e1007595 (2018). 498 Citations 26 Altmetric Metrics Abstract Topoisomerases introduce transient DNA breaks to relax supercoiled DNA, remove catenanes and enable chromosome segregation. Moreover, it has recently become possible to examine proteolysed TOP1-DPCs using a specific antibody that recognizes the TOP1DNA cleavage junctions246,247,248,249. It is likely that the sites of damage and whether topoisomerases are trapped during transcription or replication, or whether the damage occurs in highly proliferative cells such as haematopoietic progenitors or in highly differentiated cells such as neurons, are germane to repair pathway choice. Sarni, D. et al. J. Biol. It is the only known enzyme to actively contribute negative supercoiling to DNA . However, the frequency of ribonucleotide misincorporation is so high147,148 that, when embedded ribonucleotides are not removed by RNAse H2, TOP1 converts them into SSBs with 3 ends bearing a 2,3-cyclophosphate145 (Figs 4,5). This review describes the landmark discovery of topoisomerase inhibitors and interfacial inhibitors and a paradigm for pharmacology. 77, 8191 (2020). (TDPs). Manthei, K. A. Targeting topoisomerase I in the era of precision medicine. Gangloff, S., MacDonald, J. P., Bendixen, C., Arthur, L. & Rothstein, R. The yeast type 1 topoisomerase Top3 interacts with Sgs1, a DNA helicase homolog: a potential eukaryotic reverse gyrase. they prevent completion of the catalytic cycle of topo II but do not stabilize the DNA cleavage complex. Recent studies provide evidence that, as part of the dissolvasome complex, the helicase activity of BLM coupled with the single-strand passage activity of TOP3A ensures telomere integrity both in alternative lengthening of telomeres cells, which represent approximately 1015% of cancers, and in normal cells that use telomerase to maintain their telomeres126,127. This comprehensive review complements the present Review. Biochem. Lieber, M. R. Mechanisms of human lymphoid chromosomal translocations. 1f,g). Biochem. Type IIB enzymes show important structural differences, but are evolutionarily related to the type IIA enzymes. 8, 1704 (2019). Both TOP1 and TOP2 can act behind transcription complexes to remove Sc (Fig. Nevertheless, the technical challenges of assessing local changes in DNA topology in live . Y.P. This has led to the classification of topos into two types: type I, which catalyze reactions involving transient single-stranded breaks, and type II, which catalyze reactions involving transient double-stranded breaks (Fig. Morimoto, H. et al. 1). The aspartic protease Ddi1 contributes to DNAprotein crosslink repair in yeast. Each break results from the. Role of topoisomerase in transcriptional regulation, World Health Organization's List of Essential Medicines, "Diversity and Functions of Type II Topoisomerases", "An activity from mammalian cells that untwists superhelical DNA--a possible swivel for DNA replication (polyoma-ethidium bromide-mouse-embryo cells-dye binding assay)", "DNA gyrase: an enzyme that introduces superhelical turns into DNA", "Mechanism of action of nalidixic acid: purification of Escherichia coli nalA gene product and its relationship to DNA gyrase and a novel nicking-closing enzyme", "T4 DNA-delay proteins, required for specific DNA replication, form a complex that has ATP-dependent DNA topoisomerase activity", "On the Replication of Desoxyribonucleic Acid (Dna)", "Topological challenges to DNA replication: conformations at the fork", "Supercoiling of the DNA template during transcription", "The Stringent Response Inhibits DNA Replication Initiation in E. coli by Modulating Supercoiling of, "Widespread distribution of archaeal reverse gyrase in thermophilic bacteria suggests a complex history of vertical inheritance and lateral gene transfers", "Structural studies of type I topoisomerases", "The ancestral role of ATP hydrolysis in type II topoisomerases: prevention of DNA double-strand breaks", "Topoisomerase VI is a chirally-selective, preferential DNA decatenase", "Drugging topoisomerases: lessons and challenges", "DNA topoisomerases and their poisoning by anticancer and antibacterial drugs", "Interfacial inhibitors: targeting macromolecular complexes", "Targeting bacterial topoisomerase I to meet the challenge of finding new antibiotics", "Quinolones: Mechanism, Lethality and Their Contributions to Antibiotic Resistance", "The Microbial Toxin Microcin B17: Prospects for the Development of New Antibacterial Agents", "A strand-passage conformation of DNA gyrase is required to allow the bacterial toxin, CcdB, to access its binding site", "Direct control of type IIA topoisomerase activity by a chromosomally encoded regulatory protein", "The pentapeptide-repeat protein, MfpA, interacts with mycobacterial DNA gyrase as a DNA T-segment mimic", "Pentapeptide repeat protein QnrB1 requires ATP hydrolysis to rejuvenate poisoned gyrase complexes", "Mechanism of antitumor drug action: poisoning of mammalian DNA topoisomerase II on DNA by 4'-(9-acridinylamino)-methanesulfon-m-anisidide", "Topoisomerase II Poisons: Converting Essential Enzymes into Molecular Scissors", "The indenoisoquinoline noncamptothecin topoisomerase I inhibitors: update and perspectives", "Emerging themes in neuronal activity-dependent gene expression", "BRCA1-BARD1 regulates transcription through modulating topoisomerase II", "A nucleotide resolution map of Top2-linked DNA breaks in the yeast and human genome", "Pausing sites of RNA polymerase II on actively transcribed genes are enriched in DNA double-stranded breaks", "A role of DNA-PK for the metabolic gene regulation in response to insulin", "Transcriptional elongation requires DNA break-induced signalling", "Glucocorticoid Receptor Transcriptional Activation via the BRG1-Dependent Recruitment of TOP2 and Ku70/86", "Profiling DNA break sites and transcriptional changes in response to contextual fear learning", https://en.wikipedia.org/w/index.php?title=Topoisomerase&oldid=1142251510, Removes (-), but not (+) supercoils. PLoS Genet. This article provides the first evidence that TOP3B acts as a dual RNA and DNA topoisomerase. Topoisomerase Assays - PMC - National Center for Biotechnology Information 3, 430440 (2002). Drug Metab. Topoisomerase activity is particularly increased in rapidly dividing and in cancer cells. NET-CAGE characterizes the dynamics and topology of human transcribed cis-regulatory elements. Blood 105, 21242131 (2005). Maede, Y. et al. Nat. Smc5/6 mediated sumoylation of the Sgs1Top3Rmi1 complex promotes removal of recombination intermediates. Mol. Topoisomerase II interacts with cohesin and CTCF at topological domain borders. Nucleic Acids Res. Although rare compared with the high lethality of the initial cancers, t-AML can be devastating for those individuals affected. Further studies are warranted to explore whether the sensitivity of malignant tumours to camptothecin and etoposide and the carcinogenic consequence of TOPccs are related to the UPS or SPRTN pathways, and whether the genomic instability of RuijsAalfs syndrome is related to the accumulation of unrepaired TOP-DPCs. Catalytic intermediates of topoisomerases are normally transient because topoisomerase cleavage complexes (TOPccs) are self-reversible (Supplementary Fig. DNA gyrase - Wikipedia Blood 117, 21372145 (2011). Temime-Smaali, N. et al. A. These sites co-localize with the ChIPseq peaks of the cohesin subunit SCC1 (also known as RAD21)89. Targeting DNA topoisomerase II in cancer chemotherapy - Nature The potential activity of TOP3A for removing hemicatenanes during replication in human cells needs to be further established. Cell 159, 16651680 (2014). 11, 1318 (2020). Mol. In mouse embryonic fibroblasts, loss of ATM and TDP2 together (but not separately) causes a significant delay in the repair of DSBs induced by etoposide282. Bloom syndrome has recently been linked with genetic alterations in TOP3A187 and in the dissolvasome component RMI2 (ref.188), which is consistent with the fact that TOP3A and BLM cooperate in the dissolvasome complex6,189 to suppress sister chromatid exchanges161,190 and HDR191 and contribute to the resolution of stalled replication forks192. Both TDP2 and MRE11 remove TOP2 adducts (Fig. Although these proteins are not viable as antibacterials, their mode of action could inspire the development of novel antibacterial compounds. Herbaux, C. et al. The topoisomerases act by transiently cutting one or both strands of the DNA. The first type II topoisomerase to be discovered was DNA gyrase from bacteria, by Martin Gellert and coworkers in 1976,[5] and also characterized by Nicholas Cozzarelli and co-workers. TDP1 activity is also controlled by its SUMOylation266, its phosphorylation by ATM and DNA-PK267, and its recruitment by poly(ADP-ribose) polymerase 1 (PARP1)268,269. Cell Rep. 35, 108977 (2021). Kouzine, F., Levens, D. & Baranello, L. DNA topology and transcription. TOP2 has also been shown to activate the transcription of MYC by oestrogens, which has been linked with oncogenesis80,85,86,87,88. Yet knocking out TOP1MT impairs liver regeneration and tumour growth by reducing the translation of genes encoded in mitochondria174,175,176,177. Thank you for visiting nature.com. Liu, L. F. & Wang, J. C. Supercoiling of the DNA template during transcription. Despite their spectacular success, resistance to FQs is a serious problem. Naughton, C. et al. Histone H2AX phosphorylated at Ser139; a sensitive biomarker of DNA double-strand breaks (DSBs). Bunch, H. et al. 20, 39773987 (2000). Cell Biol. Position-specific effects of base mismatch on mammalian topoisomerase II DNA cleaving activity. Behind the transcription complex, excessive Sc must be removed to prevent formation of R-loops and alternative DNA structures169 (not shown). A class of enzymes called DNA topoisomerases removes helical twists by cutting a DNA strand and then resealing the cut. F1000Res. TOP1, TOP1MT, TOP2A and TOP2B bind double-stranded DNA; TOP3A and TOP3B bind single-stranded DNA or RNA. TDP2-dependent non-homologous end-joining protects against topoisomerase II-induced DNA breaks and genome instability in cells and in vivo. Topoisomerase 1 (TOP1), mitochondrial TOP1 (TOP1MT), TOP2A and TOP2B remove both Sc+ and Sc by incising double-stranded DNA; TOP3B (and TOP3A) relax hyper-negative supercoiling by nicking and closing single-stranded DNA segments. 27, 16781691 (2013). The roles of topoisomerases in centromeres and telomeres warrant further investigations, as these regions consist of DNA repeats prone to recombination and formation of non-canonical DNA structures130,131. The covalent catalytic intermediates are referred to as the TOPccs. Because of its potent ligase activity across non-canonical and non-homologous structures152,156,157, including Holliday junctions158, TOP1 may have additional DNA repair and rejoining activities, warranting further investigations. Advanced Research Networks (to S.T.). DNA gyrase is an essential bacterial enzyme that catalyzes the ATP-dependent negative super-coiling of double-stranded closed-circular DNA. The TOP1 requirement in front of transcription complexes to remove Sc+ (Fig. 4, 2478 (2013). TOP2A is essential for decatenating daughter DNA molecules and resolving sister chromatid intertwines1,8,48 (Fig. Tsai, H. Z., Lin, R. K. & Hsieh, T. S. Drosophila mitochondrial topoisomerase III affects the aging process via maintenance of mitochondrial function and genome integrity. 182, 58555864 (2009). Genet. Nucleic Acids Res. Khiati, S. et al. 5a). Additionally, the endonuclease complexes MUS81EME1 (refs271,272) and XPFERCC1 (refs273,274,275) can excise TOP1-DPCs (Fig. Centromeric and telomeric regions and ribosomal DNA appear to retain catenated segments until anaphase8. Mol. Res. Such functional DPCs would be self-reversible, and if not reversible they would be removed by the repair pathways described below. Transcription 7, 7583 (2016). Wu, J., Feng, L. & Hsieh, T. S. Drosophila topo III is required for the maintenance of mitochondrial genome and male germ-line stem cells. Piazza, A. Cell Rep. 16, 368378 (2016). Boteva, L. et al. Type I topoisomerase - Wikipedia Clin. Whereas the Sc+ generated ahead of the RNA polymerase II (Pol II) complex is readily removed by TOP1 (ref.56), the Sc behind Pol II (Fig. Finally, the detailed location and roles of topoisomerases at centromeres and telomeres, and how topoisomerases are coordinated with chromatin remodelling factors and the architecture of chromatin and chromosomes, represent promising areas of investigation. 70, 40674084 (2013). Chem. Thus, a residual amount of MRE11 activity appears sufficient for the repair of TOP2ccs. ATM may phosphorylate MRE11 and its cofactor, CtIP (also known as RBBP8), as these proteins are known to be phosphorylated by ATM and promote NHEJ of etoposide-induced TOP2-DPCs in G1 phase283. Mre11 is essential for the removal of lethal topoisomerase 2 covalent cleavage complexes. Cell Rep. 28, 31673181.e6 (2019). Ahmad, M., Xu, D. & Wang, W. Type IA topoisomerases can be magicians for both DNA and RNA in all domains of life. Nat. 37, 738748 (2009). Defective DNA single-strand break repair in spinocerebellar ataxia with axonal neuropathy-1. Cristini, A. et al. Genes Dev. Nat Rev Mol Cell Biol 23, 407427 (2022). Such knots have been proposed to contribute to chromatin organization9,10 and recombination11 in yeast models. TOP2 synergizes with BAF chromatin remodeling for both resolution and formation of facultative heterochromatin. Krivtsov, A. V. et al. Selective oxidation of DNA topoisomerase 1 induces systemic sclerosis in the mouse. 89, 102837 (2020). 5a) can be initiated by ribonucleotides incorporated into the DNA by replicative polymerases148,218 (Fig.