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Molecular mechanisms of topoisomerase 2 DNA–protein crosslink resolution

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Abstract

The compaction of DNA and the continuous action of DNA transactions, including transcription and DNA replication, create complex DNA topologies that require Type IIA Topoisomerases, which resolve DNA topological strain and control genome dynamics. The human TOP2 enzymes catalyze their reactions via formation of a reversible covalent enzyme DNA–protein crosslink, the TOP2 cleavage complex (TOP2cc). Spurious interactions of TOP2 with DNA damage, environmental toxicants and chemotherapeutic “poisons” perturbs the TOP2 reaction cycle, leading to an accumulation of DNA–protein crosslinks, and ultimately, genomic instability and cell death. Emerging evidence shows that TOP2-DNA protein crosslink (DPC) repair entails multiple strand break repair activities, such as removal of the poisoned TOP2 protein and rejoining of the DNA ends through homologous recombination (HR) or non-homologous end joining (NHEJ). Herein, we discuss the molecular mechanisms of TOP2-DPC resolution, with specific emphasis on the recently uncovered ZATTZnf451-licensed TDP2-catalyzed TOP2-DPC reversal mechanism.

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Acknowledgements

This research was supported by the intramural research program of the US National Institutes of Health (NIH), National Institute of Environmental Health Sciences (NIEHS) Grant 1Z01ES102765 to R.S.W.

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  1. Department of Health and Human Services, Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, US National Institutes of Health, Research Triangle Park, NC, USA

    Amanda A. Riccio, Matthew J. Schellenberg & R. Scott Williams

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Riccio, A.A., Schellenberg, M.J. & Williams, R.S. Molecular mechanisms of topoisomerase 2 DNA–protein crosslink resolution. Cell. Mol. Life Sci. 77, 81–91 (2020). https://doi.org/10.1007/s00018-019-03367-z

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