Topoisomerase
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Topoisomerases (type I: EC 5.99.1.2, type II: EC 5.99.1.3) are enzymes that act on the topology of DNA, discovered by James C. Wang. [1] The double-helical configuration that DNA strands naturally reside in 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 of DNA.
The insertion of viral DNA into chromosomes and other forms of recombination can also require the action of topoisomerases.
Many drugs operate through interference with the topoisomerases. The broad-spectrum fluoroquinolone antibiotics act by disrupting the function of bacterial type II topoisomerases. Some chemotherapy drugs work by interfering with topoisomerases in cancer cells: type 1 is inhibited by irinotecan and topotecan, while type 2 is inhibited by etoposide and teniposide.
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[edit] Topological problems
There are three main types of topology; supercoiling, knotting and catenation. When outside of replication or transcription DNA needs to be kept as compact as possible and these three states help this cause. However when transcription or replication occur DNA needs to be free and these states seriously hinder the processes. Topoisomerases can fix this and are separated into two types separated by the number of strands cut in one round of action.
[edit] Type I topoisomerases
Both type I and type II topoisomerases change the supercoiling of DNA. Type I topoisomerases function by nicking one of the strands of the DNA double helix, twisting it around the other strand, and re-ligating the nicked strand. This is not an active process in the sense that energy in the form of ATP is not spent by the topoisomerase during uncoiling of the DNA; rather, the torque present in the DNA drives the uncoiling. Type I enzymes can be further subdivided into type IA and type IB, based on their chemistry of action. Type IA topoisomerases change the linking number of a circular DNA strand by units of strictly 1, wherease Type IB topoisomerases change the linking number by multiples of 1. All topoisomerases form a phosphotyrosine intermediate between the catalytic tyrosine of the enzyme and the scissile phosphoryl of the DNA backbone. Type IA topoisomerases form a covalent linkage between the catalytic tyrosine and the 5'-phosphoryl while type IB enzymes form a covalent 3'-phosphotyrosine intermediate. Apart from these similarities, they have very different mechanisms of action, have different crystal structures and appear not to have similar evolutionary ancestors.
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Type II topoisomerases cut both strands of the DNA helix simultaneously. Once cut, the ends of the DNA are separated, and a second DNA duplex is passed through the break. Following passage, the cut DNA is resealed. This reaction allows type II topoisomerases to increase or decrease the linking number of a DNA loop by 2 units, and promotes chromosome disentanglement. For example, DNA gyrase, a type II topoisomerase observed in E. coli and most other prokaryotes, introduces negative supercoils and decreases the linking number by 2. Gyrase also is able to remove knots from the bacterial chromosome. There are two subclasses of type II topoisomerases, type IIA and IIB. Type IIA topoisomerases include the enzymes DNA gyrase, eukaryotic topoisomerase II, and bacterial topoisomerase IV. Type IIB topoisomerases are structurally and biochemically distinct, and comprise a single family member, topoisomerase VI. Type IIB topoisomerases are found in archaea and some higher plants. In cancers, the topoisomerase IIalpha is highly expressed in highly proliferating cells. In certain cancers, such as peripheral nerve sheath tumors, high expression of its encoded protein is also associated to poor patient survival.
Catenation is where two circular DNA strands are linked together like chain links. This occurs after DNA replication where two single strands are catenated can still replicate but cannot separate into the two daughter cells. As Type II topoisomerses break a double strand they can fix this state (Type I topoisomerases could only do this if there was a single strand nick) and the correct chromosome number can remain in daughter cells. As linear DNA in eukaryotes is so long they can be thought of as circular and Type II topoisomerases are needed for the same reason. [Bold text]klklkokukjmkuijvkfildioioi0[ie[[[Link title]<math>Insert non-formatted text here</math>#REDIRECT [[Insert text]]]]
[edit] References
Champoux JJ (2001) DNA Topoisomerases: Structure, Function, and Mechanism Annual Review of Biochemistry 70: 369-413[2]
