what is the role of topoisomerase

Natl Acad. Science 332, 15611564 (2011). Nature 436, 10531057 (2005). CellMinerCDB for integrative cross-database genomics and pharmacogenomics analyses of cancer cell lines. Other topological difficulties arise during replication and chromatin loop formation when duplex DNA molecules form catenanes. 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). Chem. The 3 ends of the break can undergo resection followed by gap filling. This relation with endogenous base damage suggests that physiological TOP2cc trapping occurs more frequently than is commonly appreciated240. Manville, C. M. et al. The functions of the SMC5SMC6 complex are less known and are discussed only briefly here. Curr. 1eg; Supplementary Table 1). 1a,b). Int. Pourquier, P. & Pommier, Y. Topoisomerase I-mediated DNA damage. Non-SMC element 2 (NSMCE2) of the SMC5/6 complex helps to resolve topological stress. Mistry, A. R. et al. USA 110, E35873594 (2013). Towards a therapy for Angelman syndrome by targeting a long non-coding RNA. 6, eaba6290 (2020). Gomez-Herreros, F. et al. It refers to the number of times the two strands of the duplex make a complete 360 degree turn. 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. Article SMC5SMC6 has been proposed to function in promoting Top2-mediated resolution of sister chromatid intertwines, and for recruiting the yeast dissolvasome complex94,95. TOP2A, but not TOP2B, readily relaxes this Sc+25, suggesting the existence of a fine-tuned balance between TOP2A and condensins8. 8, 1704 (2019). 70, 40674084 (2013). 1. Patel, A. G. et al. J. Hum. The existence of redundant mechanisms that repair topoisomerase-induced genomic damage begs the question of repair pathway choice and selection. TOP2 chromatin binding is dependent on and proportional to cohesin binding100. Karras, G. I. et al. Hsiang, Y. H. & Liu, L. F. Evidence for the reversibility of cellular DNA lesion induced by mammalian topoisomerase II poisons. PubMedGoogle Scholar. Natl Acad. TOP1 is essential both for early development in mice and for viability of vertebrate cells166 (Table1; Supplementary Table 1). Considering the viability of TDP2-deficient mice280 and the pivotal role of TDP2 in the repair of etoposide-induced TOP2ccs264,280,284, future studies are warranted to understand why TDP2 fails to suppress the endogenous accumulation of lethal TOP2ccs. Although rare compared with the high lethality of the initial cancers, t-AML can be devastating for those individuals affected. h | During mitosis, TOP2A is part of the chromosome scaffold comprising condensin complexes, whereas TOP1 is present in loop domains. 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. Seita, J. (NHEJ). TOP2ccs are also a well-established source of DNA damage and carcinogenic mutations by endogenous and environmental agents17. EMBO J. 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. Cancer Cell 13, 432440 (2008). J. Med. Advanced microscopy methods and chromosome conformation capture-based techniques that identify DNA sequences in close proximity, owing to chromatin folding, have revealed the high-order organization and dynamic folding of the genome in interphase cells and led to the identification of chromatin loops and TADs89,90,91. Vanden Broeck, A. et al. Cell 36, 943953 (2009). Aminocoumarins (Fig. J. Biol. Branched DNA structures consisting of four double-stranded arms joined together. Li, T. K. et al. Int. Google Scholar. 6, 10191 (2015). Pourquier, P. et al. USA 115, E10642E10651 (2018). We discuss the expanding number of redundant pathways that repair TOP-DPCs, and the defects in those pathways, which are increasingly recognized as source of genomic damage leading to neurological diseases and cancer. Dynamic behavior of DNA topoisomerase II in response to DNA double-strand breaks. Natl Acad. Proc. Piskadlo, E. & Oliveira, R. A. 22, 27672772 (2008). TOP2-DPCs can also be proteolysed by non-proteasomal pathways245,248,254,255,256, and non-proteolytically by TDP2 following their SUMOylation and unfolding by ZNF451 (refs257,258,259) (Fig. Mol. 11, 3940 (2020). Cell Rep. 21, 34833497 (2017). 180, 409418 (1989). Dev. Following the excision of TOP-DPCs, cells restore the DNA by filling the gaps and resealing the DNA breaks. This article reveals the importance of TOP3B for neuronal functions. Waldman, T. Emerging themes in cohesin cancer biology. TOP2B: the first thirty years. 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. Pommier, Y. McClendon, A. K., Rodriguez, A. C. & Osheroff, N. Human topoisomerase II rapidly relaxes positively supercoiled DNA: implications for enzyme action ahead of replication forks. Recently, we showed that TOP3B-DPCs are also removed by the UPS pathway2. Mutation of TDP1, encoding a topoisomerase I-dependent DNA damage repair enzyme, in spinocerebellar ataxia with axonal neuropathy. To that effect, TOP-DPCs are subjected to proteolytic degradation2,201,244,245 (Fig. Thakurela, S. 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. Chem. Reijns, M. A. M. et al. CAS ACS Chem. Nitiss, J. L. DNA topoisomerase II and its growing repertoire of biological functions. Biol. Where Lk refers to the number of times the two strands are linked, Tw refers to the number of helical turns in the DNA, measured relative to the helical axis, and Wr quantifies the coiling of the path of the DNA helix in space and is often equated with 'supercoiling'. Das, B. Article EMBO J. USA 104, 92429247 (2007). DSB end resection during HDR generates 3 single-strand tails, and thereby removes 5 blocking adducts such as TOP2-DPCs. 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. Despite their spectacular success, resistance to FQs is a serious problem. Topoisomerases in DNA replication. PLoS Genetics 16, e1009256 (2020). Human Tdp1 cleaves a broad spectrum of substrates including phosphoamide linkages. a | Twin supercoiled domain model54. Sci. Google Scholar. 28, 19471954 (2000). they prevent completion of the catalytic cycle of topo II but do not stabilize the DNA cleavage complex. 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. Nat. Yet knocking out TOP1MT impairs liver regeneration and tumour growth by reducing the translation of genes encoded in mitochondria174,175,176,177. 26, 33973409 (2007). B. et al. 164, 164167 (2006). [55] The components of the non-homologous end joining DNA repair pathway were essential to the closing of the DNA double-strand break.[52]. Genes. Loop extrusion as a mechanism for formation of DNA damage repair foci. Husain, A. et al. 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. Natl. 1e). Uuskula-Reimand, L. & Wilson, M. D. Break check: transcription-driven topoisomerase II collisions near chromatin loop anchors are hotspots for DNA damage and translocations. Li, W. & Wang, J. C. Mammalian DNA topoisomerase III is essential in early embryogenesis. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Adv. Cell 168, 644656 (2017). Proc. The amount of DNA twist, which is the number of crossovers of the two strands across each other; writhe is a measure of the double helix winding around itself. Failure to separate these strands leads to cell death. J. Biol. Involvement of topoisomerase II. Leukemia 19, 22892295 (2005). & Pasero, P. Homologous recombination and Mus81 promote replication completion in response to replication fork blockage. 3ad). Nat. ). Vaccinia virus topoisomerase I specifically recognizes the pentameric sequence 5-(C/T)CCTT-3 and forms a covalent bond with the phosphate group attached to the 3 thymidine. DNA topoisomerase I differentially modulates R-loops across the human genome. Another duplex, termed the transport segment (T-segment), is captured by an ATP-operated clamp and passed through a transient break in the G-segment, involving 5 phosphotyrosine linkages in both strands, before it is released through the C-gate and the G-segment is re-ligated (Fig. Biol. Nucleus 5, 195202 (2014). Similarly, initiation of replication from the main bacterial origin oriC also requires negative supercoiling. As cancer survival statistics have improved, t-AML cases have increased; up to 15% of all acute myeloid leukaemia (AML) cases can be classified as t-AML289. Topoisomerases are an increasingly recognized source of genome instability. Joshi, R. S., Nikolaou, C. & Roca, J. Perillo, B. et al. 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. 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. 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. Decatenation reactions are carried out by TOP2 enzymes1 (Fig. Most clinically. & Pommier, Y. Debulking of topoisomerase DNAprotein crosslinks (TOP-DPC) by the proteasome, non-proteasomal and non-proteolytic pathways. 9, 190222 (2019). USA 90, 66566660 (1993). B., Dexheimer, T. S., Maddali, K. & Pommier, Y. Cell Biol. eg | Proposed roles of cohesins, TOP1 and TOP2B in assembly of chromatin loops and topologically associating domains (TADs): cohesin and condensin complexes are loaded onto DNA during G1 phase of cell cycle, along with transcription resumption after mitosis (part e); transcription-driven negative DNA supercoiling is proposed to extrude chromatin loops (parts ad) and form TADs, with TOP2B removing associated topological barriers such as DNA crossovers and catenanes (part f), resulting in TAD formation (part g). Topoisomerase 3 knockout mice show transcriptional and behavioural impairments associated with neurogenesis and synaptic plasticity. Nucleic Acids Res. 6) have been highly-successful. Acad. Riccio, A. 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. Pommier, Y. Drugging topoisomerases: lessons and challenges. 1b). Mol. It was the type I topoisomerase. Due to the inaccessible location of the covalent tyrosylDNA bonds inside the TOPccs (Supplementary Fig. Serbyn, N. et al. Type II enzymes are mechanistically distinct from type I in being ATP-dependent and transiently cleaving both DNA strands rather than just one. Chem. & Vaughan, A. T. M. Apoptotic triggers initiate translocations within the MLL gene involving the nonhomologous end joining repair system. Mol. Science 286, 552555 (1999). In fission yeast, this pathway depends on the Smc5SMC6 complex, replication signals and Top2 activity114. [33] Additional cytotoxicity stems from redox reactions involving anthracyclines that generate reactive oxygen species. Deiss, K. et al. Natl Acad. Structural basis for allosteric regulation of human topoisomerase II. Ma, J. UBC13-mediated ubiquitin signaling promotes removal of blocking adducts from DNA double-strand breaks. Sci. Efficient substrate resealing requires the alignment of the ends of the broken DNA inside the TOPcc (Supplementary Fig. 201), this review provides details and references for the redundant pathways that repair abortive TOPccs, complementary to the current Review. Rev. Sci. Secondary leukemias induced by topoisomerase-targeted drugs. Zhang, Y. W. et al. USA 82, 31243128 (1985). 4c). Pommier, Y. et al. Another mutagenic consequence of irreversible TOP1ccs results from their collisions with replication forks (Figs4c,6). Subsequently, a TOP1cc formed 5 adjacent to the ribonucleotide (possibly by the same TOP1 molecule sliding back on the DNA) (Fig. Endogenous topoisomerase II-mediated DNA breaks drive thymic cancer predisposition linked to ATM deficiency. Transcription 7, 7583 (2016). DNA gyrase, or simply gyrase, is an enzyme within the class of topoisomerase and is a subclass of Type II topoisomerases that reduces topological strain in an ATP dependent manner while double-stranded DNA is being unwound by elongating RNA-polymerase or by helicase in front of the progressing replication fork.
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