Abstract
Human topoisomerases comprise a family of six enzymes: two type IB (TOP1 and mitochondrial TOP1 (TOP1MT), two type IIA (TOP2A and TOP2B) and two type IA (TOP3A and TOP3B) topoisomerases. In this Review, we discuss their biochemistry and their roles in transcription, DNA replication and chromatin remodelling, and highlight the recent progress made in understanding TOP3A and TOP3B. Because of recent advances in elucidating the high-order organization of the genome through chromatin loops and topologically associating domains (TADs), we integrate the functions of topoisomerases with genome organization. We also discuss the physiological and pathological formation of irreversible topoisomerase cleavage complexes (TOPccs) as they generate topoisomerase DNA–protein crosslinks (TOP-DPCs) coupled with DNA breaks. We discuss the expanding number of redundant pathways that repair TOP-DPCs, and the defects in those pathways, which are increasingly recognized as source of genomic damage leading to neurological diseases and cancer.
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Acknowledgements
The authors’ understanding of topoisomerases stems from the dedication and constant discussions of members of the Laboratory of Molecular Pharmacology, Developmental Therapeutics Branch, Center for Cancer Research, the Intramural Program of the National Cancer Institute, National Institutes of Health (NIH) (Z01-BC-006161). They thank K. W. Kohn, who first hypothesized that doxorubicin and other anthracycline anticancer drugs act by forming protein-associated DNA breaks, which are now referred to as TOPccs. Y.P. and A.N. are supported by the Center for Cancer Research of the US National Cancer Institute (CCR-NCI) (Z01 BC 006161 and Z01 BC 006150 to Y.P.). This work was also supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (16H12595 and 16H06306) (to S.T.) and JSPS Core-to-Core Program, A. Advanced Research Networks (to S.T.). The authors thank X. Yang, postdoctoral fellow in the Pommier group, for his contribution to Supplementary Fig. 1. They are also grateful to the three reviewers who provided multiple suggestions and careful corrections.
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Glossary
- Tyrosyl-DNA phosphodiesterases
-
(TDPs). Referring to TDP1 and TDP2, enzymes that excise topoisomerase–DNA crosslinks by hydrolysing 3′-phosphodiester and 5′-phosphodiester bonds, respectively. TDP2 also excises TOP3–RNA crosslinks.
- DNA supercoiling
-
The amount of DNA twist, which is the number of crossovers of the two strands across each other; writhe is a measure of the double helix winding around itself. Positive DNA supercoiling (Sc+) is defined by increased twist and/or writhe; negative DNA supercoiling (Sc–) is the opposite.
- Hemicatenanes
-
Crossovers of two strands of DNA originating from different DNA molecules.
- Holliday junctions
-
Branched DNA structures consisting of four double-stranded arms joined together. Double Holliday junctions form hemicatenanes that are resolved by the Bloom syndrome protein (BLM)–topoisomerase 3A (TOP3A)–RecQ-mediated genome instability proteins (RMI1/2) (BTR) dissolvasome complex.
- Topologically associating domains
-
(TADs). In interphase chromosomes, genomic regions in which interactions between loci are enriched compared with interactions with loci outside the domain.
- Structural maintenance of chromosomes
-
(SMC). SMC complexes are ATPase complexes that tether and organize chromatin by forming chromatin loops and ensuring sister chromatid cohesion.
- Homology-directed repair
-
(HDR). A replication-associated DNA double-strand break (DSB) repair pathway that uses a homologous sequence as a template for resynthesizing a missing DNA segment. Its classical form is homologous recombination and its common effector is RAD51.
- γH2AX
-
Histone H2AX phosphorylated at Ser139; a sensitive biomarker of DNA double-strand breaks (DSBs).
- TOPcc trapping
-
Stabilization of topoisomerase cleavage complexes (TOPccs) by inhibition of DNA end rejoining by a drug molecule bound at the interface of the DNA break and the enzyme or by DNA lesions that misalign the broken DNA ends, thereby preventing the release of the topoisomerase.
- Non-homologous end joining
-
(NHEJ). The prominent DNA double-strand break (DSB) repair pathway, which rapidly joins adjacent DNA ends. Its main effectors are Ku70–Ku80 and DNA-dependent protein kinase (DNA-PK).
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Pommier, Y., Nussenzweig, A., Takeda, S. et al. Human topoisomerases and their roles in genome stability and organization. Nat Rev Mol Cell Biol 23, 407–427 (2022). https://doi.org/10.1038/s41580-022-00452-3
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DOI: https://doi.org/10.1038/s41580-022-00452-3
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