topoisomerases

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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 halt DNA replication. (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 agents 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 strands. 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.

See also

• DNA topology
• Supercoil
• TOP1
• Type II topoisomerase

References

• Pommier, Yves (May 28, 2010). "DNA topoisomerases and their poisoning by anticancer and antibacterial drugs". Chemistry & Biology. 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 978-0-87969-879-9

External links

• DNA Topoisomerases at the US National Library of Medicine Medical Subject Headings (MeSH)

UpToDate Contents

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• 1. フルオロキノロン類、ドキシサイクリン、およびトリメトプリムスルファメトキサゾールに対する肺炎レンサ球菌の耐性 resistance of streptococcus pneumoniae to the fluoroquinolones doxycycline and trimethoprim sulfamethoxazole
• 2. 進行性多巣性白質脳症：治療および予後 progressive multifocal leukoencephalopathy treatment and prognosis

English Journal

• Luciferase inhibition by a novel naphthoquinone.

• Bedford R, Lepage D, Hoffmann R, Kennedy S, Gutschenritter T, Bull L, Sujijantarat N, Dicesare JC, Sheaff RJ.SourceDepartment of Chemistry and Biochemistry, The University of Tulsa, Tulsa, OK, United States.
• Journal of photochemistry and photobiology. B, Biology.J Photochem Photobiol B.2012 Feb 6;107:55-64. Epub 2011 Dec 8.
• The novel naphthoquinone 12,13-dihydro-N-methyl-6,11,13-trioxo-5H-benzo[4,5]cyclohepta[1,2-b]naphthalen-5,12-imine (hereafter called TU100) was created as a potential chemotherapeutic agent. Previous work showed it is an irreversible inhibitor of type I and II topoisomerases that alkylates specific
• PMID 22197716

Japanese Journal

• Molecular Analysis of Levofloxacin-resistant Streptococcus pneumoniae in Japan

• SHOJI Hisashi,TAKUMA Takahiro,NIKI Yoshihito
• The Showa University Journal of Medical Sciences 26(3), 181-190, 2014
• … Quinolone resistance has been attributed to amino acid mutations in the type II topoisomerases of pathogens. … We also sequenced the quinolone resistance-determining regions (QRDRs) in type II topoisomerases and analyzed the relationship between minimum inhibitory concentration (MIC) and six specific mutations (Ser81 or Glu85 in GyrA, Asp435 in GyrB, Ser79 or Asp83 in ParC, and Asp435 in ParE). …
• NAID 130004841522

• Inhibitory effects of catechin derivatives on mammalian DNA polymerase and topoisomerase activities and mouse one-cell zygote development(BIOCHEMICAL ENGINEERING)

• Yoshida Naoko,Kuriyama Isoko,Yoshida Hiromi [他],Mizushina Yoshiyuki
• Journal of bioscience and bioengineering 115(3), 303-309, 2013-03
• … In this study, the inhibitory activities against DNA polyinerases (pols) and DNA topoisomerases (topos) by eight major green tea catechin derivatives (flavan-3-ols) were investigated. …
• NAID 110009596105

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