DNA topoisomerase

DNAトポイソメラーゼ

関

DNA topoisomerase I、topoisomerase I、type I DNA topoisomerase

WordNet

1. the 4th letter of the Roman alphabet (同)d

PrepTutorEJDIC

1. deuteriumの化学記号
2. deoxyribonucleic acidディオキシリボ核酸

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2012/03/08 20:48:24」(JST)

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[Wiki en表示]

Topoisomerases (type I: EC 5.99.1.2, type II: EC 5.99.1.3) are enzymes that regulate the overwinding or underwinding of DNA. The winding problem of DNA arises due to the intertwined nature of its double helical structure. For example, during DNA replication, DNA becomes overwound ahead of a replication fork. If left unabated, this tension would eventually grind replication to a halt (a similar event happens during transcription.)

In order to help overcome these types of topological problems caused by the double helix, topoisomerases bind to either single-stranded or double-stranded DNA and cut the phosphate backbone of the DNA. This intermediate break allows the DNA to be untangled or unwound, and, at the end of these processes, the DNA backbone is resealed again. Since the overall chemical composition and connectivity of the DNA does not change, the tangled and untangled DNAs are chemical isomers, differing only in their global topology, thus their name. Topoisomerases are isomerase enzymes that act on the topology of DNA.

Discovery

The first topoisomerase, E. coli topo I, was discovered by James C. Wang.

Function

The double-helical configuration that DNA strands naturally reside makes them difficult to separate, and yet they must be separated by helicase proteins if other enzymes are to transcribe the sequences that encode proteins, or if chromosomes are to be replicated. In so-called circular DNA, in which double helical DNA is bent around and joined in a circle, the two strands are topologically linked, or knotted. Otherwise identical loops of DNA, having different numbers of twists, are topoisomers, and cannot be interconverted by any process that does not involve the breaking of DNA strands. Topoisomerases catalyze and guide the unknotting or unkinking of DNA by creating transient breaks in the DNA using a conserved Tyrosine as the catalytic residue.

The insertion of viral DNA into chromosomes and other forms of recombination can also require the action of topoisomerases.

Clinical significance

See also topoisomerase inhibitor

Many drugs operate through interference with the topoisomerases [1]. The broad-spectrum fluoroquinolone antibiotics act by disrupting the function of bacterial type II topoisomerases. These small molecule inhibitors act as efficient anti-bacterial by hijacking the natural ability of topoisomerase to create breaks in chromosomal DNA.

Some chemotherapy drugs called topoisomerase inhibitors work by interfering with mammalian-type eukaryotic topoisomerases in cancer cells. This induces breaks in the DNA that ultimately lead to programmed cell death (apoptosis). This DNA-damaging effect, outside of its potentially curative properties, may lead to secondary neoplasms in the patient.^{[citation needed]}

Topoisomerase I is the antigen recognized by Anti Scl-70 antibodies in scleroderma.

Topological problems

There are three main types of topology: supercoiling, knotting and catenation. Outside of the essential processes of replication or transcription, DNA must be kept as compact as possible, and these three states help this cause. However, when transcription or replication occur, DNA must be free, and these states seriously hinder the processes. In addition, during replication, the newly replicated duplex of DNA and the original duplex of DNA become intertwined and must be completely separated in order to ensure genomic integrity as a cell divides. As a transcription bubble proceeds, DNA ahead of the transcription fork becomes overwound, or positively supercoiled, while DNA behind the transcription bubble becomes underwound, or negatively supercoiled. As replication occurs, DNA ahead of the replication bubble becomes positively supercoiled, while DNA behind the replication fork becomes entangled forming precatenanes. One of the most essential topological problem occurs at the very end of replication, when daughter chromosomes must be fully disentangled before mitosis occurs. Topoisomerase IIA plays an essential role in resolving these topological problems.

Classes

Topoisomerases can fix these topological problems and are separated into two types separated by the number of strands cut in one round of action: Both these classes of enzyme utilize a conserved tyrosine. However these enzymes are structurally and mechanistically different. For a video of this process see: http://www.youtube.com/watch?v=EYGrElVyHnU&feature=related.

• Type I topoisomerase cuts one strand of a DNA double helix, relaxation occurs, and then the cut strand is reannealed. Cutting one strand allows the part of the molecule on one side of the cut to rotate around the uncut strand, thereby reducing stress from too much or too little twist in the helix. Such stress is introduced when the DNA strand is "supercoiled" or uncoiled to or from higher orders of coiling. Type I topoisomerases are subdivided into two subclasses: type IA topoisomerases, which share many structural and mechanistic features with the type II topoisomerases, and type IB topoisomerases, which utilize a controlled rotary mechanism. Examples of type IA topoisomerases include topo I and topo III. In the past, type IB topoisomerases were referred to as eukaryotic topo I, but IB topoisomerases are present in all three domains of life. It is interesting to note that type IA topoisomerases form a covalent intermediate with the 5' end of DNA, while the IB topoisomerases form a covalent intermediate with the 3' end of DNA. Recently, a type IC topoisomerase has been identified, called topo V. While it is structurally unique from type IA and IB topoisomerases, it shares a similar mechanism with type IB topoisomerase.

• Type II topoisomerase cuts both strands of one DNA double helix, passes another unbroken DNA helix through it, and then reanneals the cut strand. It is also split into two subclasses: type IIA and type IIB topoisomerases, which share similar structure and mechanisms. Examples of type IIA topoisomerases include eukaryotic topo II, E. coli gyrase, and E. coli topo IV. Examples of type IIB topoisomerase include topo VI. Type II topisomerases utilize ATP hydrolysis.

Topoisomerase	IA	IB	IIA	IIB
Metal Dependence	Yes	No	Yes	Yes
ATP Dependence	No	No	Yes	Yes
Single- or Double-Stranded cleavage?	SS	SS	DS	DS
Cleavage Polarity	5'	3'	5'	5'
Change in L	±1	±N	±2	±2

Both type I and type II topoisomerases change the linking number (L) of DNA. Type IA topoisomerases change the linking number by one, type IB and type IC topoisomerases change the linking number by any integer, while type IIA and type IIB topoisomerases change the linking number by two.

References

• Pommier, Yves (May 28, 2010). "DNA topoisomerases and their poisoning by anticancer and antibacterial drugs". Chemistry & Biology. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20534341. Retrieved May 28, 2010. 

Further reading

• James C. Wang (2009) Untangling the Double Helix. DNA Entanglement and the Action of the DNA Topoisomerases, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 2009. 245 pp. ISBN 9780879698799

See also

• DNA topology
• Supercoil
• TOP1
• Type II topoisomerase

External links

• MeSH DNA+Topoisomerases

UpToDate Contents

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• 1. DNAによる親子鑑定 parentage testing using dna
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• 3. 次世代DNAシークエンシングの原理および臨床応用 principles and clinical applications of next generation dna sequencing
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• 5. 強皮症の概要および分類 overview and classification of scleroderma disorders

English Journal

• Salicylate, a Catalytic Inhibitor of Topoisomerase II, Inhibits DNA Cleavage and Is Selective for the α Isoform.

• Bau JT, Kang Z, Austin CA, Kurz EU.Author information Southern Alberta Cancer Research Institute and Department of Physiology and Pharmacology, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada (J.T.B., Z.K., E.U.K.); and Institute for Cellular and Molecular Biosciences, Newcastle University, Newcastle upon Tyne, Tyne and Wear, United Kingdom (C.A.A.).AbstractTopoisomerase II (topo II) is a ubiquitous enzyme that is essential for cell survival through its role in regulating DNA topology and chromatid separation. Topo II can be poisoned by common chemotherapeutics (such as doxorubicin and etoposide), leading to the accumulation of cytotoxic enzyme-linked DNA double-stranded breaks. In contrast, nonbreak-inducing topo II catalytic inhibitors have also been described and have more limited use in clinical chemotherapy. These agents, however, may alter the efficacy of regimens incorporating topo II poisons. We previously identified salicylate, the primary metabolite of aspirin, as a novel catalytic inhibitor of topo II. We have now determined the mechanism by which salicylate inhibits topo II. As catalytic inhibitors can act at a number of steps in the topo II catalytic cycle, we used multiple independent, biochemical approaches to interrogate the catalytic cycle. Furthermore, as mammalian cells express two isoforms of topo II (α and β), we examined whether salicylate was isoform selective. Our results demonstrate that salicylate is unable to intercalate DNA, and does not prevent enzyme-DNA interaction, nor does it promote stabilization of topo IIα in closed clamps on DNA. Although salicylate decreased topo IIα ATPase activity in a dose-dependent noncompetitive manner, this was secondary to salicylate-mediated inhibition of DNA cleavage. Surprisingly, comparison of salicylate's effects using purified human topo IIα and topo IIβ revealed that salicylate selectively inhibits the α isoform. These findings provide a definitive mechanism for salicylate-mediated inhibition of topo IIα and provide support for further studies determining the basis for its isoform selectivity.
• Molecular pharmacology.Mol Pharmacol.2014 Feb;85(2):198-207. doi: 10.1124/mol.113.088963. Epub 2013 Nov 12.
• Topoisomerase II (topo II) is a ubiquitous enzyme that is essential for cell survival through its role in regulating DNA topology and chromatid separation. Topo II can be poisoned by common chemotherapeutics (such as doxorubicin and etoposide), leading to the accumulation of cytotoxic enzyme-linked
• PMID 24220011

• Ochratoxin A induces karyomegaly and cell cycle aberrations in renal tubular cells without relation to induction of oxidative stress responses in rats.

• Taniai E, Yafune A, Nakajima M, Hayashi SM, Nakane F, Itahashi M, Shibutani M.Author information Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan; Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193, Japan.AbstractOchratoxin A (OTA) is a renal carcinogen that induces karyomegaly in target renal tubular cells of the outer stripe of the outer medulla (OSOM). This study was performed to clarify the relationship between oxidative stress and the karyomegaly-inducing potential involving cell cycle aberration of OTA in the OSOM. Rats were treated with OTA for 28 days in combination with enzymatically modified isoquercitrin (EMIQ) or α-lipoic acid (ALA) as antioxidants. OTA increased the mRNA levels of the antioxidant enzyme-related genes Gpx1, Gpx2, Gstm1 and Nfe2l2, but did not increase the levels of Gsta5, Keap1, Nqo1, Hmox1, Aldh1a1, Por, Prdx1 and Txn1. OTA also did not change the levels of thiobarbituric acid-reactive substances, glutathione disulfide/reduced glutathione, and the immunoreactive tubular cell distribution of nuclear factor erythroid 2-related factor 2 in the OSOM. Co-treatment with EMIQ or ALA did not cause any changes in these parameters. As previously reported, OTA increased cell proliferation activity, apoptosis and immunohistochemical cellular distributions of molecules suggestive of induction of DNA damage and cell cycle aberrations involving spindle checkpoint disruption and cell cycle arrest. However, co-treatment with EMIQ or ALA did not suppress these changes, and ALA co-treatment increased the cell proliferation activity induced by OTA. These results suggest that OTA facilitates cell cycling involving cell cycle aberrations and apoptosis as a basis of the mechanism behind the development of karyomegaly and subsequent carcinogenicity targeting the OSOM, without relation to induction of oxidative stress. On the other hand, ALA may promote the OTA-induced proliferation of carcinogenic target cells.
• Toxicology letters.Toxicol Lett.2014 Jan 3;224(1):64-72. doi: 10.1016/j.toxlet.2013.10.001. Epub 2013 Oct 11.
• Ochratoxin A (OTA) is a renal carcinogen that induces karyomegaly in target renal tubular cells of the outer stripe of the outer medulla (OSOM). This study was performed to clarify the relationship between oxidative stress and the karyomegaly-inducing potential involving cell cycle aberration of OTA
• PMID 24120684

• Antiviral Activity of (+)-Rutamarin against Kaposi's Sarcoma-Associated Herpesvirus by Inhibition of the Catalytic Activity of Human Topoisomerase II.

• Xu B, Wang L, González-Molleda L, Wang Y, Xu J, Yuan Y.Author information Institute of Human Virology, Ministry of Education, Sun Yat-Sen University, Guangzhou, Guangdong, China.AbstractKaposi's sarcoma-associated herpesvirus (KSHV) is an etiological agent of several AIDS-associated malignancies, including Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD). Its lytic replication cycle has been proven to be critical for the pathogenesis of KSHV-associated diseases. In KS lesions, lytic viral replication, production of virion particles, and reinfection of endothelial cells are essential to sustain the population of infected cells that otherwise would be quickly lost as spindle cells divide. Thus, antivirals that block KSHV replication could be a strategy in the treatment of KSHV-associated diseases. However, there is no effective anti-KSHV drug currently available. Our previous work showed that human topoisomerase II (Topo II) is indispensable for KSHV lytic replication and is suggested to be an effective target for antiviral drugs. Here, we report the discovery and characterization of a novel catalytic inhibitor of human Topo IIα, namely, (+)-rutamarin. The binding mode of (+)-rutamarin to the ATPase domain of human Topo IIα was established by docking and validated by molecular dynamics (MD) simulations. More importantly, (+)-rutamarin efficiently inhibits KSHV lytic DNA replication in BCBL-1 cells with a half-maximal inhibitory concentration (IC50) of 1.12 μM and blocks virion production with a half-maximal antiviral effective concentration (EC50) of 1.62 μM. It possesses low cytotoxicity, as indicated by the selectivity index (SI) of 84.14. This study demonstrated great potential for (+)-rutamarin to become an effective drug for treatment of human diseases associated with KSHV infection.
• Antimicrobial agents and chemotherapy.Antimicrob Agents Chemother.2014 Jan;58(1):563-73. doi: 10.1128/AAC.01259-13. Epub 2013 Dec 2.
• Kaposi's sarcoma-associated herpesvirus (KSHV) is an etiological agent of several AIDS-associated malignancies, including Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD). Its lytic replication cycle has been proven to be critical for the pathogenesi
• PMID 24295975

Japanese Journal

• Smarcal1 promotes double-strand-break repair by nonhomologous end-joining.

• Keka Islam Shamima,Mohiuddin,Maede Yuko,Rahman Md Maminur,Sakuma Tetsushi,Honma Masamitsu,Yamamoto Takashi,Takeda Shunichi,Sasanuma Hiroyuki
• Nucleic acids research, 2015-06-18
• … シムケ免疫不全・骨形成不全症の原因遺伝子SMARCAL1は、DNA二重鎖切断損傷からゲノムを守る. … 2015-06-23.Smarcal1 is a SWI/SNF-family protein with an ATPase domain involved in DNA-annealing activities and a binding site for the RPA single-strand-DNA-binding protein. …
• NAID 120005617590

• Nuclear dynamics of topoisomerase II beta reflects its catalytic activity that is regulated by binding of RNA to the C-terminal domain

• Onoda Akihisa,Hosoya Osamu,Sano Kuniaki,Kiyama Kazuko,Kimura Hiroshi,Kawano Shinji,Furuta Ryohei,Miyaji Mary,Tsutsui Ken,Tsutsui Kimiko M.
• Nucleic Acids Research 42(14), 9005-9020, 2014-07-17
• … DNA topoisomerase II (topo II) changes DNA topology by cleavage/re-ligation cycle(s) and thus contributes to various nuclear DNA transactions. …
• NAID 120005553910

• An Easy-to-use Genotoxicity Assay Using EGFP-MDC1-expressing Human Cells

• Matsuda Shun,Matsuda Ryo,Matsuda Yoko,Yanagisawa Shin-ya,Ikura Masae,Ikura Tsuyoshi,Matsuda Tomonari
• Genes and Environment 36(1), 17-28, 2014
• … Histone H2AX phosphorylated at Ser139 (γ-H2AX) is a useful biomarker for DNA double-strand breaks. … Mediator of DNA damage checkpoint 1 (MDC1) is a central adaptor protein which recruits various DNA damage response proteins to γ-H2AX and thus forms nuclear foci in the same location as γ-H2AX in response to DNA damage. …
• NAID 130004481211

Related Links

• DNA Topoisomerase I｜タカラバイオ株式会社 遺伝子工学研究

触媒する反応 1．環状のスーパーコイル分子のスーパーコイル状態を解消する。 2．一本鎖の環状DNA分子内に、DNA鎖の結び目を作ったり（knotting）、それをほどいたりする（unknotting）作用がある。 3．互いに相補的な塩基配列を持つ ...

• DNA Topoisomerase

DNA Topoisomerase Functions of DNA Topoisomerases There are a number of different types of topoisomerases, each specialising in a different aspect of DNA manipulation. Accessing DNA During transcription and DNA ...

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★リンクテーブル★

リンク元	「topoisomerase I」「DNAトポイソメラーゼ」
拡張検索	「type I DNA topoisomerase」「type II DNA topoisomerase」「DNA topoisomerase I」「DNA topoisomerase II」「eukaryotic type I DNA topoisomerase」
関連記事	「D」「DNA」

「topoisomerase I」

　　[★]

ト・イソメラーゼI

関

DNA topoisomerase、DNA topoisomerase I、type I DNA topoisomerase

「DNAトポイソメラーゼ」

　　[★]

英

DNA topoisomerase

関

トポイソメラーゼ

「type I DNA topoisomerase」

　　[★]

I型DNAト・イソメラーゼ、DNAト・イソメラーゼI

関

DNA topoisomerase、DNA topoisomerase I、topoisomerase I

「type II DNA topoisomerase」

　　[★]

II型DNAト・イソメラーゼ、DNAト・イソメラーゼII

関

DNA topoisomerase II、topoisomerase II

「DNA topoisomerase I」

　　[★]

DNAト・イソメラーゼI

関

DNA topoisomerase、topoisomerase I、type I DNA topoisomerase

「DNA topoisomerase II」

　　[★]

DNAト・イソメラーゼII

関

topoisomerase II、type II DNA topoisomerase

「eukaryotic type I DNA topoisomerase」

　　[★]

• 真核生物ト・イソメラーゼI

関

eukaryotic topoisomerase I

「D」

　　[★]

• アスパラギン酸
• ジヒドロウリジン
• 遠位の distal,
• うつ病 depression
• 下行結腸 descending colon(大腸内視鏡検査の結果を記載するときに用いる)

　 　

「DNA」

　　[★]

英

deoxyribonucleic acid

同

デオキシリボ核酸

関

リボ核酸 RNA