Type II topoisomerase

  Type II topoisomerases cut both strands of the DNA helix simultaneously in order to change the linking number of the molecule.

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Function

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 religated. This reaction allows type II topoisomerases to increase or decrease the linking number of a DNA loop by 2 units, and promotes chromosome disentanglement. Reactions involving the increase in supercoiling require ATP. 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.

Eukaryotic type II topoisomerase cannot introduce supercoils; it can only relax them. This is thought to be unnecessary because the binding of DNA by histones increases potential superhelicity.

Classification

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

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 already 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 being without ends and Type II topoisomerases are needed for the same reason.

Inhibition

Type 2 topoisomerases are inhibited by etoposide, Novobiocin and teniposide.

The experimental anti-tumor drug m-AMSA (4'-(9'-acridinylamino)methanesulfon-m-anisidide) also inhibits type 2 topoisomerase.^[1]

References

1. ^ Willmore E, de Caux S, Sunter NJ, et al (2004). "A novel DNA-dependent protein kinase inhibitor, NU7026, potentiates the cytotoxicity of topoisomerase II poisons used in the treatment of leukemia". Blood 103 (12): 4659–65. doi:10.1182/blood-2003-07-2527. PMID 15010369.