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  • Review Article
  • Published:

Topoisomerase-mediated chromosomal break repair: an emerging player in many games

Key Points

  • Topoisomerases are elegant biological tools that have evolved to resolve nucleic acid entanglements during replication, transcription and recombination.

  • Trapping of topoisomerases on DNA results in protein-linked DNA breaks (PDBs), which are widely exploited by topoisomerase-targeting cancer therapies.

  • PDB precision scissors (tyrosyl-DNA phosphodiesterase 1 (TDP1) and TDP2) are enzymes that are capable of liberating stalled topoisomerases from DNA termini without cleaving the DNA.

  • The inappropriate repair of PDBs can promote cancer in a tissue-specific manner — a process that is closely linked to gene transcription.

  • Transcription-associated PDBs can cause gene deletion, chromosomal rearrangement and therapy-induced secondary malignancy.

Abstract

The mammalian genome is constantly challenged by exogenous and endogenous threats. Although much is known about the mechanisms that maintain DNA and RNA integrity, we know surprisingly little about the mechanisms that underpin the pathology and tissue specificity of many disorders caused by defective responses to DNA or RNA damage. Of the different types of endogenous damage, protein-linked DNA breaks (PDBs) are emerging as an important player in cancer development and therapy. PDBs can arise during the abortive activity of DNA topoisomerases, a class of enzymes that modulate DNA topology during several chromosomal transactions, such as gene transcription and DNA replication, recombination and repair. In this Review, we discuss the mechanisms underpinning topoisomerase-induced PDB formation and repair with a focus on their role during gene transcription and the development of tissue-specific cancers.

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Figure 1: Precision scissors for PDB repair: TDP1 and TDP2.
Figure 2: The catalytic cycle and physiological substrates of TDPs.
Figure 3: Overview of chromosomal protein-linked DNA break repair.
Figure 4: Topoisomerases and transcription-associated genome instability.
Figure 5: Protein-linked DNA breaks and chromosomal rearrangement.

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Acknowledgements

This work is funded by a Wellcome Trust Investigator Award (103844) and a Lister Institute of Preventative Medicine Fellowship to S.F.E.-K. The authors thank P. Jeggo, A. Goldman, K. Caldecott, A. Lehmann and members of the El-Khamisy laboratory for helpful discussions. The authors apologize to colleagues whose primary research articles are not cited owing to space restrictions.

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PowerPoint slides

Glossary

Topological entanglements

The coiling and winding of the DNA double helix.

Transesterification reaction

The process of exchanging the organic group of an ester with the organic group of an alcohol.

Supercoiling

The over- or underwinding of the DNA double helix.

R-loops

The association of a stretch of single-stranded RNA with a complementary region of DNA, whereby one DNA strand is displaced as a loop.

Alternative NHEJ

Repair of DNA double-strand breaks by an error-prone non-homologous end-joining (NHEJ) pathway that is independent of DNA ligase IV.

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Ashour, M., Atteya, R. & El-Khamisy, S. Topoisomerase-mediated chromosomal break repair: an emerging player in many games. Nat Rev Cancer 15, 137–151 (2015). https://doi.org/10.1038/nrc3892

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