Topoisomerase

  Topoisomerases (type I: EC 5.99.1.2, type II: EC 5.99.1.3) are isomerase enzymes that acts on the topology of DNA. It was first discovered by Harvard Professor James C. Wang.^[1]

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Function

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.

Clinical significance

See also topoisomerase inhibitor

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.
• type 2 is inhibited by etoposide and teniposide.

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. 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.

Types

Topoisomerases can fix these topological problems and are separated into two types separated by the number of strands cut in one round of action:

• Type I topoisomerase cuts one strand, passes the other through it then reanneals the cut strand.
• Type II topoisomerase cuts both strands, and passes an unbroken double strand through it then reanneals the cut strand.

Both type I and type II topoisomerases change the linking number of DNA.

References

1. ^ http://www.nasonline.org/site/PageServer?pagename=AWARDS_molbio]

• Champoux JJ (2001) DNA Topoisomerases: Structure, Function, and Mechanism Annual Review of Biochemistry 70: 369-413[1]

See also

• DNA topology
• Supercoil
• TOP1