Nucleic Acids Res. Zhang, H. et al. Cell 184, 26182632.e17 (2021). Endogenous DNA 3 blocks are vulnerabilities for BRCA1 and BRCA2 deficiency and are reversed by the APE2 nuclease. Int. Sci. Mol. Cell Rep. 33, 108569 (2020). 9, 190222 (2019). EMBO J. This article provides an extensive review of topoisomerase inhibitors. USA 109, 1612516130 (2012). 24, 344352 (2017). Rev. Topoisomerases facilitate transcription of long genes linked to autism. Coordinated regulation of mitochondrial topoisomerase IB with mitochondrial nuclear encoded genes and MYC. Boteva, L. et al. 42, 668675 (2010). Synergistic coordination of chromatin torsional mechanics and topoisomerase activity. 7) and its close relative teniposide (VM-26) are epipodophyllotoxin derivatives obtained from the rhizome of wild mandrake that target topo II by stabilizing the covalent cleavage complex and preventing religation of the cleaved DNA. Loop extrusion as a mechanism for formation of DNA damage repair foci. Piazza, A. Biophys. Pommier, Y., Sun, Y., Huang, S. N. & Nitiss, J. L. Roles of eukaryotic topoisomerases in transcription, replication and genomic stability. We discuss their specific and overlapping roles as regulators of nucleic acid topology and metabolism, thereby complementing other recent reviews1,3,4,5,6,7,8. 19, 114129 (2014). Google Scholar. Zhao, B. et al. a | Overall scheme for conversion of topoisomerase DNAprotein crosslinks (TOP-DPCs) into protein-free DNA breaks201. Mao, Y., Desai, S. D., Ting, C. Y., Hwang, J. L. & Liu, L. F. 26S proteasome-mediated degradation of topoisomerase II cleavable complexes. Overexpression of TDP2 partially rescues the lethality of MRE11-deficient cells, indicating that stalled TOP2ccs generate lethal DSBs in cycling cells. Li, W. & Wang, J. C. Mammalian DNA topoisomerase III is essential in early embryogenesis. Proc. Biol. Res. What are properties of eukaryotes Topoisomerase I? Neurosci. Nat. Topoisomerase III is required for normal proliferation and telomere stability in alternative lengthening of telomeres. Cell Rep. 28, 31673181.e6 (2019). 8, 7587 (2016). Cell Cycle 9, 274278 (2010). TOP2ccs are also a well-established source of DNA damage and carcinogenic mutations by endogenous and environmental agents17. Mol. 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. Tyrosyl-DNA phosphodiesterase 1 (TDP1) repairs DNA damage induced by topoisomerases I and II and base alkylation in vertebrate cells. Strumberg, D. et al. 7, 1691905 (2020). Cell 149, 10081022 (2012). Biol. Hudson, D. F. et al. This comprehensive review complements the present Review. Biol. Chem. 16, 12281237 (2013). Natl. Nat. Sekiguchi, J. Potts, P. R., Porteus, M. H. & Yu, H. Human SMC5/6 complex promotes sister chromatid homologous recombination by recruiting the SMC1/3 cohesin complex to double-strand breaks. Indeed, translocation junction sequences are consistent with the erroneous joining of heterologous chromosome segments by NHEJ, or by the variant pathway alternative end joining296,297. USA 93, 785789 (1996). Defining the molecular interface that connects the Fanconi anemia protein FANCM to the Bloom syndrome dissolvasome. 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. Mauritzson, N. et al. & Hammarsten, O. Cell 183, 2845 (2020). A. M. et al. PubMed Central 11, 1962 (2020). J. Biol. The first DNA topoisomerase was discovered in bacteria by James Wang in 1971 and was initially named (omega) protein;[3] it is now called Escherichia coli (E. coli) topoisomerase I (topo I) and is a representative of the type IA family of enzymes. Nitiss, J. L. Targeting DNA topoisomerase II in cancer chemotherapy. Cancer Res. Meyer, C. et al. Mol. Article The stability of TDP1 is regulated by the deubiquitylase UCHL3 (ref.265). A secondary TOP1 forms a TOP1cc 5 of the nick, and the resulting short oligonucleotide bearing the 2,3-cyclophosphate is released. Van Waardenburg, R. C. A. M. et al. Nat. Gene regulation and priming by topoisomerase II in embryonic stem cells. & Pommier, Y. Debulking of topoisomerase DNAprotein crosslinks (TOP-DPC) by the proteasome, non-proteasomal and non-proteolytic pathways. EMBO J. 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. 5). Broderick, L. et al. EMBO J. Topoisomerase II represses transcription by enforcing promoter-proximal pausing. TOP3A, in addition to its roles in resolving double Holliday junctions and suppressing sister chromatid exchanges, is involved in DNA end resection160 and homology-directed repair (HDR)6,28,161,162. 91-92, 102849102849 (2020). This relation with endogenous base damage suggests that physiological TOP2cc trapping occurs more frequently than is commonly appreciated240. 10, 3644 (2019). 48, 1194211957 (2020). Nat. Nucleic Acids Res. iScience 23, 101027101027 (2020). Cancer 16, 387398 (2016). R-loops forming due to insufficient TOP1 activity induce DSBs (bottom)72. d | Insufficient topoisomerase activity can result in excessive positive DNA supercoiling (Sc+) that arrests transcription and replication, and in negative supercoiling (Sc) that induces formation of R-loops and alternative DNA structures, including G quadruplexes (G4) and Z-DNA67,165. Lieber, M. R. Mechanisms of human lymphoid chromosomal translocations. Mutation of TDP1, encoding a topoisomerase I-dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy. The occurrence of TOP1ccs across nicks can also induce recombinogenic DSBs1,211,213 (Fig. Biol. TOP1 and TOP1MT (type IB topoisomerases) cleave only one strand of double-stranded DNA by forming the 3-phosphotyrosyl linkage (3 DNAprotein crosslinks (DPCs)) (Supplementary Fig. Cell Cycle 18, 23772384 (2019). Nucleic Acids Res. 1). 35, 250260 (2021). New topo I inhibitors, the indenoisoquinolines and fluoroindenoisoquinolines, overcome the limitations of CPT derivatives and are currently in clinical trials. Sci. A topology-centric view on mitotic chromosome architecture. 3). 4c). Failure to separate these strands leads to cell death. Wiley Interdiscip. Individuals with genetic inactivation of TOP3B suffer from severe neurological symptoms, including cognitive impairment, which have been related to the RNA topoisomerase activity of TOP3B26,197. Rev. This article provides the first evidence that TOP3B acts as a dual RNA and DNA topoisomerase. Cell (2021). Lee, K. C., Bramley, R. L., Cowell, I. G., Jackson, G. H. & Austin, C. A. Proteasomal inhibition potentiates drugs targeting DNA topoisomerase II. Berti, M. et al. Genes. Cell 179, 604618 (2019). The prominent DNA double-strand break (DSB) repair pathway, which rapidly joins adjacent DNA ends. 46, 16481660 (2018). 26, 47204731 (2007). Cell Rep. 23, 33523365 (2018). Schalbetter, S. A., Mansoubi, S., Chambers, A. L., Downs, J. Type II enzymes are mechanistically distinct from type I in being ATP-dependent and transiently cleaving both DNA strands rather than just one. Lee, C. M., Wang, G., Pertsinidis, A. Cell 168, 644656 (2017). Karras, G. I. et al. Krivtsov, A. V. et al. It represents an appropriate, but nonselective target for anticancer therapy. Stantial, N. et al. Looping-out mechanism for resolution of replicative stress at telomeres. Condensin also generates Sc+ in an ATP-dependent manner within those loops, which further contributes to chromosome compaction. Whereas TOP2A and Top2 are essential components of the chromosome mitotic scaffold, TOP1 has also been observed within mitotic chromosomal loops, where it may act to dissipate excessive supercoiling123,124 (Fig. Chem. Cancer Res. It was the type I topoisomerase. The energetics and physiological impact of cohesin extrusion. The C-terminal domain of RNA polymerase II is modified by site-specific methylation. 40, e105393 (2021). The functions of the SMC5SMC6 complex are less known and are discussed only briefly here. Cancer 5, 943955 (2005). Scharf, S. et al. 89, 102837 (2020). Genome organization drives chromosome fragility. Cell 159, 16651680 (2014). Androgen deprivation followed by acute androgen stimulation selectively sensitizes AR-positive prostate cancer cells to ionizing radiation. To that effect, TOP-DPCs are subjected to proteolytic degradation2,201,244,245 (Fig. EMBO J. This situation is commonly observed following treatment with etoposide227,358. Rev. TOP2A, but not TOP2B, readily relaxes this Sc+25, suggesting the existence of a fine-tuned balance between TOP2A and condensins8. The coincidence of TOP2B locations with TAD borders has been related to an interaction of TOP2B with the amino terminus of CTCF99,100,106 (Fig. Sci. This article uses the End-seq method developed by the authors to map TOP2 sites and their processing to frank breaks and translocations. Hudson, J. J., Chiang, S. C., Wells, O. S., Rookyard, C. & El-Khamisy, S. F. SUMO modification of the neuroprotective protein TDP1 facilitates chromosomal single-strand break repair. Cancer Res. Commun. In these complexes, topoisomerases I and II create single- and double-stranded breaks, respectively. Physical proximity of sister chromatids promotes Top2-dependent intertwining. Additional details are provided for the TOP3 enzymes, which were not covered in depth in our previous Review1. Katyal, S. et al. However, the type II enzymes, DNA gyrase and DNA topoisomerase IV, have enjoyed enormous success as targets for the widely-used fluoroquinolone antibiotics, (Fig. We describe the molecular mechanisms by which abortive TOPccs damage the genome and the multiple pathways that repair those cellular lesions and how they relate to genomic instability. An in vivo topoisomerase II cleavage site and a DNase I hypersensitive site colocalize near exon 9 in the MLL breakpoint cluster region. Identifying cis elements for spatiotemporal control of mammalian DNA replication. Rev. In the case of gyrase, a substantial amount of the free energy from ATP hydrolysis is transduced into torsional stress in DNA, i.e. 11, 3613 (2020). However, yeast Top2 has recently been shown to promote sister chromatid intertwines during prophase while removing them at the onset of anaphase122. 18, 2751 (2017). TOP1cc, TOP1 cleavage complex. We emphasize the need to further define the roles of topoisomerases in genome organization and stability, as well as the increasingly recognized implication of topoisomerases in generating deleterious genomic lesions associated with irreversible topoisomerase cleavage complexes (TOPccs). Proc. Genet. Abstract. 41, 98489857 (2013). Topoisomerase- Definition, Types, Structure, Functions, Mechanism & Wang, J. C. Identification of the yeast TOP3 gene product as a single strand-specific DNA topoisomerase. Therefore it is the sole type I topoisomerase classified as EC 5.6.2.2 (Table 1). 1d). J. In addition, these enzymes fine-tune the steady-state level of DNA supercoiling both to facilitate protein interactions with the DNA and to . RNase H2-initiated ribonucleotide excision repair. Proc. Sci. Left unresolved, links between replicated DNA will impede cell division. Abnormal rejoining of TOP2-induced DSBs has recently been reported to account for short duplications203 (Fig. 473, 169180 (2001). Nature 590, 660665 (2021). Increased negative supercoiling of mtDNA in TOP1mt knockout mice and presence of topoisomerases II and II in vertebrate mitochondria. McClendon, A. K., Rodriguez, A. C. & Osheroff, N. Human topoisomerase II rapidly relaxes positively supercoiled DNA: implications for enzyme action ahead of replication forks. Alterations of DNA repair genes in the NCI-60 cell lines and their predictive value for anticancer drug activity. Chem. Adv. 36, 361373 (2017). Cellular roles of DNA topoisomerases: a molecular perspective Bjornsti, M. A. Excessive torsional strain first changes the helical twist (number of crossovers of the two strands across each other) until the entire duplex of DNA (or RNA) winds around itself (writhe) and flips into alternative plectonemic structures with crossover segments and entanglements. Kwan, K. Y. et al. 20, 48734881 (2014). 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. J. Mol. Vanden Broeck, A. et al. Canela, A. et al. Nat. However, CPT derivatives suffer from limitations associated with toxicity and limited therapeutic half-lives due to chemical instability. Distribution bias and biochemical characterization of TOP1MT single nucleotide variants. Type II topoisomerases change DNA topology by breaking and rejoining double-stranded DNA. TOP2A dysfunction has been proposed to activate a decatenation checkpoint that arrests cells at G2M phase transition to protect them against chromosomal damage8. Science 319, 202206 (2008). Thomas, A. UBC13-mediated ubiquitin signaling promotes removal of blocking adducts from DNA double-strand breaks. Because of the potential danger of topoisomerases, it is likely that their activity is controlled and restricted to proper sites of action. Res. [31], For the non-specialist perhaps the most important aspect of topoisomerases is their role as drug targets both for antibacterial and anti-cancer chemotherapy; several topoisomerase-targeted antibacterial and anti-cancer drugs are listed among the 2019 World Health Organization Model List of essential Medicines. Activation of topoisomerase II-mediated excision of chromosomal DNA loops during oxidative stress. Specifically, they intercalate into the DNA and prevent the DNA religation step of the topoisomerase reaction (Fig. Yet knocking out TOP1MT impairs liver regeneration and tumour growth by reducing the translation of genes encoded in mitochondria174,175,176,177. 1, 417424 (1995). Natl Acad. 1e). & Vaughan, A. T. M. Apoptotic triggers initiate translocations within the MLL gene involving the nonhomologous end joining repair system. Note that TOP2A and TOP2B also generate DNA single-strand breaks (SSBs) when only one protein of the dimer breaks the DNA1. An indel signature consisting of 24 base pair duplications and due to a TOP2A mutation (K473N) that traps TOP2A has been found in patient tumours and proposed to be named as the ID-TOP2A signature364. 3ad). TOP2-DPCs can also be directly excised by endonucleases100,241,270 (Fig. Rev. Topo IIdependent double-strand DNA breaks and components of the DNA damage repair machinery are important for rapid expression of immediate early genes, as well as for signal-responsive gene regulation. 1c; Supplementary Fig. Without topoisomerase activity, the formation of Sc+ in front of the replication fork and the resulting tightening of the DNA duplex with the potential formation of plectonemes would block replisome movement. Cell 142, 230242 (2010). Blood 117, 21372145 (2011). Since the overall chemical composition and connectivity of the DNA do not change, the DNA substrate and product are chemical isomers, differing only in their topology. Because genes are activated by enhancers that are generally located quite a distance in cis from promoters, enhancerpromoter interactions require the formation of chromatin loops89. Despite their spectacular success, resistance to FQs is a serious problem. Genet. Because of recent advances in elucidating the high-order organization of the genome through chromatin loops and topologically associating domains (TADs), we integrate the functions of topoisomerases with genome organization. USA 115, E10642E10651 (2018). Topoisomerase 3 interacts with RNAi machinery to promote heterochromatin formation and transcriptional silencing in Drosophila. Int. Waldman, T. Emerging themes in cohesin cancer biology. Struct. Each human cell contains 2 m of DNA that are compacted into a nucleus that is 10 m in diameter (14,15).Because the genetic material is anchored to the chromosome scaffold and the two strands of the double helix are plectonemically coiled, accessing the genome is a complex topological . Because TOPccs are protein-associated DNA strand breaks, they can be mapped by pulling down the topoisomerase polypeptides to retrieve the bound DNA segments or by directly mapping the DNA breaks (the different techniques used to map TOPccs are summarized in Supplementary Box 2). Genet. Tang, Z. et al. 1). Type II topoisomerases are required for other processes such as transcription, and the precise roles of the two isoforms in these processes are a subject of current studies. PLoS ONE 4, e5859 (2009). Aragon, L. The Smc5/6 complex: new and old functions of the enigmatic long-distance relative. Stabilization of topoisomerase cleavage complexes (TOPccs) by inhibition of DNA end rejoining by a drug molecule bound at the interface of the DNA break and the enzyme or by DNA lesions that misalign the broken DNA ends, thereby preventing the release of the topoisomerase. J. Mol. 2a): TOP1 in underwound duplex DNA segments and TOP2 at crossovers between DNA duplexes. TopI enzymes are not dependent on ATP for their catalytic activity, except for reverse gyrase [ 3]. Mutagen. Topoisomerase is an enzyme tasked with cutting, or influencing DNA to repair breakage and avoid further complication when necessary. Rev. These sites co-localize with the ChIPseq peaks of the cohesin subunit SCC1 (also known as RAD21)89. Because topoisomerases are exploited as targets for a wide range of anticancer and antibacterial drugs, understanding the repair pathways of TOPccs can provide opportunities for improving the rational use of topoisomerase inhibitors and their combination with other drugs in cancer treatment. Miglietta, G., Russo, M. & Capranico, G. G-quadruplexR-loop interactions and the mechanism of anticancer G-quadruplex binders. [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. Sobek, S. et al. & Jackson, A. P. Ribonuclease H2 in health and disease. contracts here. Cell Res. In interphase chromosomes, genomic regions in which interactions between loci are enriched compared with interactions with loci outside the domain. b | In theory, polymerases transcribing in tandem could cancel supercoiling between them, which would facilitate transcript elongation. Science 286, 552555 (1999). 3, 430440 (2002). Yang, W. Topoisomerases and site-specific recombinases: similarities in structure and mechanism. Itou, J. et al. 51, 49094916 (1991). Secondary leukemias induced by topoisomerase-targeted drugs. This work was also supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (16H12595 and 16H06306) (to S.T.) Role of topoisomerase II in DNA damage response following IR and etoposide. 287, 1284812857 (2012). 1. Int. & Stasiak, A. Transcription-induced supercoiling as the driving force of chromatin loop extrusion during formation of TADs in interphase chromosomes. In the meantime, to ensure continued support, we are displaying the site without styles Hamperl, S., Bocek, M. J., Saldivar, J. C., Swigut, T. & Cimprich, K. A. Transcriptionreplication conflict orientation modulates R-loop levels and activates distinct DNA damage responses. Chem. 276, 3159031595 (2001). Cell. PubMed Central Examples of type IB topoisomerases include eukaryotic nuclear and mitochondrial topo I in addition to viral topo I, though they have been identified in all three domains of life. 307, 301307 (2003). Nucleic Acids Res. Yet their association with chromatin remodelling complexes could contribute to DNA repair135,136,137. Nat Rev Mol Cell Biol 23, 407427 (2022). TOP2 chromatin binding is dependent on and proportional to cohesin binding100. The accumulation of R-loops in the context of TOP1 deficiency is a potential source of DNA breaks and genomic instability72,73. MRE11 facilitates the removal of human topoisomerase II complexes from genomic DNA. Nat. 71, 6981 (2018). Such chromatin loops generate DNA topological and torsional constraints, which are substrates for topoisomerases (Fig. ATM-deficient mice exhibit endogenous accumulation of TOP1-DPCs and neurodegeneration250. 12, e1006483 (2016). Larcher, M. V. & Pasero, P. Top1 and Top2 promote replication fork arrest at a programmed pause site. 1e). Grimwade, D. & Enver, T. Acute promyelocytic leukemia: where does it stem from? Lee, J. H. & Berger, J. M. Cell cycle-dependent control and roles of DNA topoisomerase II. TOP2A, but not TOP2B, is cell cycle regulated1,16,24,34: it increases sharply from mid S phase through mitosis through transcriptional activation of TOP2A, stabilization of TOP2A mRNA and activation of the deubiquitylase USP15, which prevents the targeting of TOP2A for proteasomal degradation8,117. Non-proteasomal proteolysis by SPRTN repairs replication-associated TOP1-DPCs and TOP2-DPCs245, and genetic inactivation of SPRTN causes RuijsAalfs syndrome with progeroid features and hepatocellular carcinomas245,247. J. Biol. This article provides evidence for the selective activity of yeast TOP2 positive supercoils using single-molecule techniques. Following the excision of TOP-DPCs, cells restore the DNA by filling the gaps and resealing the DNA breaks. 1f,g). Neale, M. J., Pan, J. 1eg). Estrogen induces mammary ductal dysplasia via the upregulation of myc expression in a DNA-repair-deficient condition. This prior review complements the current Review with detailed biochemical and pharmacological information. Int. As the DNA is threaded through the cohesin complex, TOP2B would be strategically positioned to eliminate topological barriers and DNA entanglements such as knots, plectonemes and catenanes before the DNA can translocate through the cohesin complexes (Fig. Human topoisomerases and their roles in genome stability and & Nussenzweig, A. Endogenous DNA damage as a source of genomic instability in cancer. Struct. 6c). Wang, H. et al. Pommier, Y. et al. 45, 31063112 (1985). An RNA virus hijacks an incognito function of a DNA repair enzyme. Lai, C. H. et al. Both TOP2B and TOP2A have been proposed to regulate the promoter-proximal pause and release of Pol II at immediate-early response genes84,85,86,87, as does TOP1 (ref.56).
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