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Cellular roles of DNA topoisomerases: a molecular perspective

This article has been updated

Key Points

  • This review examines the cellular functions of the DNA topoisomerases from a mechanistic point of view. The following points are summarized.

  • Classification of DNA topoisomerases into four subfamilies IA, IB, IIA and IIB, and the unique mechanistic features of each subfamily.

  • The topological problems of various cellular transactions of DNA, such as replication and transcription, and the plausible roles of different subfamilies of DNA topoisomerases in each of these processes.

  • The presence of at least one IA enzyme in all known living organisms, and plausible roles of this subfamily that cannot be fulfilled by any of the other subfamilies of DNA topoisomerases.

  • The DNA topoisomerases presumably evolved to solve the topological problems of DNA as it became longer and longer or ring-shaped. These elegant solutions nevertheless introduce weak spots into intracellular DNA because of the necessity of transiently breaking DNA strands. So, the DNA topoisomerases might have become the unwitting targets of a plethora of natural and synthesized compounds.

Abstract

DNA topoisomerases are the magicians of the DNA world — by allowing DNA strands or double helices to pass through each other, they can solve all of the topological problems of DNA in replication, transcription and other cellular transactions. Extensive biochemical and structural studies over the past three decades have provided molecular models of how the various subfamilies of DNA topoisomerase manipulate DNA. In this review, the cellular roles of these enzymes are examined from a molecular point of view.

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Figure 1: Catalysis of transient breakage of DNA by DNA topoisomerases.
Figure 2: Molecular models for the passage of one DNA strand or double helix through another by different subfamilies of DNA topoisomerases.
Figure 3: Topological problems associated with an elongating replication fork.
Figure 4: A distinct topological problem occurs when two replication forks converge.
Figure 5: Generation of oppositely supercoiled domains by transcription.

Change history

  • 07 June 2002

    yes

Notes

  1. 1.

    *Citations to FIG 3C have been changed to read FIG 3B throughout.

  2. 2.

    *The text in parentheses has been added.

  3. 3.

    *This sentence has been added.

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Acknowledgements

I thank A. Bergerat, K. Kwan and E. Marcotte for their help in confirming the presence of at least one type IA DNA topoisomerase-coding region in genomes of known nucleotide sequences. Work in my laboratory on DNA topoisomerases has been supported mainly by grants from the National Institutes of Health. Part b in Box 2 figure is based on one by Henry M Sobel.* Footnote 3

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DATABASES

Flybase

Barren

topoisomerase I

topoisomerase II

LocusLink

BLM

RECQL4

topoisomerase IIα

topoisomerase IIβ

WRN

<i>Saccharomyces</i> Genome Database

SGS1

SPO11

topoisomerase I

topoisomerase II

topoisomerase III

TRF4

Glossary

NEGATIVELY AND POSITIVELY SUPERCOILED DNA

A loop of a double-stranded DNA segment will become contorted if one end of it is turned around its helical axis at that end while the other end is kept stationary in space (much like the spatial coiling of a rubber tubing when similarly handled). The number of supercoils that are introduced into this loop is a parameter that is used to quantify the distortion of the looped DNA segment; one negative supercoil is said to be introduced into the DNA loop by each full turn of the rotating end in the direction that tends to unwind the right-handed double helix; one positive supercoil is said to be introduced by each full turn of the rotating end in the direction that tends to overwind the right-handed double helix.

SEMICONSERVATIVE REPLICATION

A common mode of replication in which both strands of a DNA double helix are copied by the replication machinery to give a pair of progeny DNA molecules.

R-LOOPING

Refers to a structure in a double-stranded DNA segment in which a single-stranded RNA pairs with a portion of one DNA strand to displace a portion of the other DNA strand in a single-stranded state.

HOLLIDAY JUNCTION

A DNA structure named after Robin Holliday, who first described it in 1964 as a plausible recombination intermediate between a pair of homologous DNA molecules.

ENDONUCLEASE

An enzyme that catalyses hydrolytic cleavage of DNA in the middle of a DNA strand or double helix.

DNA STRAND-TRANSFERASE

An enzyme that transfers a donor group of one DNA strand (for example, a 5′ phosphoryl group) to a receiving group of another DNA strand (for example, a 3′ hydroxyl group).

BRANCH MIGRATION

The movement of a junction formed by multiple DNA or RNA strands of complementary nucleotide sequences that results from nearly simultaneous breakage and formation of base pairs among them.

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Wang, J. Cellular roles of DNA topoisomerases: a molecular perspective. Nat Rev Mol Cell Biol 3, 430–440 (2002). https://doi.org/10.1038/nrm831

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