topoisomerase - wikipedia, the free encyclopedia

TopoisomeraseFrom Wikipedia, the free encyclopedia

Topoisomerases (type I: EC 5.99.1.2 (http://enzyme.expasy.org/EC/5.99.1.2) , type II: EC 5.99.1.3(http://enzyme.expasy.org/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 tensionwould 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 bindto either single-stranded or double-stranded DNA and cut the phosphate backbone of the DNA. Thisintermediate break allows the DNA to be untangled or unwound, and, at the end of these processes, the DNAbackbone is resealed again. Since the overall chemical composition and connectivity of the DNA does notchange, the tangled and untangled DNAs are chemical isomers, differing only in their global topology, thus theirname. Topoisomerases are isomerase enzymes that act on the topology of DNA.[1]

Contents

1 Discovery2 Function3 Clinical significance4 Topological problems5 Classes6 See also7 References8 Further reading9 External links

Discovery

The first topoisomerase, E. coli topo I, was discovered by James C. Wang.[2]

Function

The double-helical configuration that DNA strands naturally reside makes them difficult to separate, and yetthey must be separated by helicase proteins if other enzymes are to transcribe the sequences that encodeproteins, or if chromosomes are to be replicated. In so-called circular DNA, in which double helical DNA isbent around and joined in a circle, the two strands are topologically linked, or knotted. Otherwise identical loopsof DNA, having different numbers of twists, are topoisomers, and cannot be interconverted by any process thatdoes not involve the breaking of DNA strands. Topoisomerases catalyze and guide the unknotting or unkinkingof DNA[3] by creating transient breaks in the DNA using a conserved Tyrosine as the catalytic residue.[1]

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

Topoisomerase - Wikipedia, the free encyclopedia http://en.wikipedia.org/wiki/Topoisomerase

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Clinical significance

See also topoisomerase inhibitor

Many drugs operate through interference with the topoisomerases [1] (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=20534341) . The broad-spectrumfluoroquinolone antibiotics act by disrupting the function of bacterial type II topoisomerases. These smallmolecule inhibitors act as efficient anti-bacterial agents by hijacking the natural ability of topoisomerase tocreate breaks in chromosomal DNA.

Some chemotherapy drugs called topoisomerase inhibitors work by interfering with mammalian-type eukaryotictopoisomerases 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 secondaryneoplasms 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 processesof 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 theprocesses. In addition, during replication, the newly replicated duplex of DNA and the original duplex of DNAbecome intertwined and must be completely separated in order to ensure genomic integrity as a cell divides. Asa transcription bubble proceeds, DNA ahead of the transcription fork becomes overwound, or positivelysupercoiled, while DNA behind the transcription bubble becomes underwound, or negatively supercoiled. Asreplication occurs, DNA ahead of the replication bubble becomes positively supercoiled, while DNA behind thereplication fork becomes entangled forming precatenanes. One of the most essential topological problem occursat 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 ofstrands cut in one round of action:[4] Both these classes of enzyme utilize a conserved tyrosine. However theseenzymes 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 isreannealed. Cutting one strand allows the part of the molecule on one side of the cut to rotate around theuncut strand, thereby reducing stress from too much or too little twist in the helix. Such stress isintroduced when the DNA strand is "supercoiled" or uncoiled to or from higher orders of coiling. Type Itopoisomerases are subdivided into two subclasses: type IA topoisomerases, which share many structuraland mechanistic features with the type II topoisomerases, and type IB topoisomerases, which utilize acontrolled 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 allthree domains of life. It is interesting to note that type IA topoisomerases form a covalent intermediatewith the 5' end of DNA, while the IB topoisomerases form a covalent intermediate with the 3' end of


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DNA. Recently, a type IC topoisomerase has been identified, called topo V. While it is structurally uniquefrom 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 helixthrough it, and then reanneals the cut strands. It is also split into two subclasses: type IIA and type IIBtopoisomerases, which share similar structure and mechanisms. Examples of type IIA topoisomerasesinclude eukaryotic topo II, E. coli gyrase, and E. coli topo IV. Examples of type IIB topoisomeraseinclude 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 changethe linking number by one, type IB and type IC topoisomerases change the linking number by any integer, whiletype IIA and type IIB topoisomerases change the linking number by two.

See also

DNA topologySupercoilTOP1Type II topoisomerase

References

^ a b Champoux JJ (2001). "DNA topoisomerases: structure, function, and mechanism". Annu. Rev. Biochem. 70:369–413. doi:10.1146/annurev.biochem.70.1.369 (http://dx.doi.org/10.1146%2Fannurev.biochem.70.1.369) .PMID 11395412 (//www.ncbi.nlm.nih.gov/pubmed/11395412) .

1.

^ "National Academy of Sciences: NAS Award in Molecular Biology" (http://www.nasonline.org/site/PageServer?pagename=AWARDS_molbio) . National Academy of Science. http://www.nasonline.org/site/PageServer?pagename=AWARDS_molbio. Retrieved 2009-01-07.

2.

^ C.Michael Hogan. 2010. Deoxyribonucleic acid. Encyclopedia of Earth. National Council for Science and theEnvironment. (http://www.eoearth.org/articles/view/158858/?topic=49496) eds. S.Draggan and C.Cleveland.Washington DC

3.

^ Wang JC (April 1991). "DNA topoisomerases: why so many?" (http://www.jbc.org/cgi/pmidlookup?view=long&pmid=1849888) . J. Biol. Chem. 266 (11): 6659–62. PMID 1849888 (//www.ncbi.nlm.nih.gov/pubmed/1849888) .http://www.jbc.org/cgi/pmidlookup?view=long&pmid=1849888.

4.

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


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Further reading

James C. Wang (2009) Untangling the Double Helix. DNA Entanglement and the Action of the DNATopoisomerases, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 2009. 245 pp. ISBN978-0-87969-879-9

External links

DNA+Topoisomerases (http://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?mode=&term=DNA+Topoisomerases) at the US National Library of Medicine Medical Subject Headings (MeSH)

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