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Roles of eukaryotic topoisomerases in transcription, replication and genomic stability

Abstract

Topoisomerases introduce transient DNA breaks to relax supercoiled DNA, remove catenanes and enable chromosome segregation. Human cells encode six topoisomerases (TOP1, TOP1mt, TOP2α, TOP2β, TOP3α and TOP3β), which act on a broad range of DNA and RNA substrates at the nuclear and mitochondrial genomes. Their catalytic intermediates, the topoisomerase cleavage complexes (TOPcc), are therapeutic targets of various anticancer drugs. TOPcc can also form on damaged DNA during replication and transcription, and engage specific repair pathways, such as those mediated by tyrosyl-DNA phosphodiesterase 1 (TDP1) and TDP2 and by endonucleases (MRE11, XPF–ERCC1 and MUS81). Here, we review the roles of topoisomerases in mediating chromatin dynamics, transcription, replication, DNA damage repair and genomic stability, and discuss how deregulation of topoisomerases can cause neurodegenerative diseases, immune disorders and cancer.

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Figure 1: Overview of eukaryotic topoisomerases.
Figure 2: Topoisomerases and transcription.
Figure 3: Functions of topoisomerases in DNA replication.
Figure 4: Topoisomerases and DNA damage.
Figure 5: TOPcc repair.

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Acknowledgements

The authors are grateful to numerous colleagues who provided helpful discussion on the diverse topics of this Review, especially D. Levens (US National Cancer Institute (NCI)), J. Berger (Johns Hopkins University, USA), N. Osheroff (Vanderbilt University, USA), P. McKinnon (St. Jude Children's Research Hospital, USA) and other members of the Pommier and Nitiss laboratories. The authors apologize to colleagues whose work could not be cited owing to space limitations. The authors' studies are supported by the Center for Cancer Research, the NCI Intramural Program (Z01 BC006161) and NCI grants CA52814 and CA187651 (to J.L.N.).

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Correspondence to Yves Pommier or John L. Nitiss.

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FURTHER INFORMATION

The Cancer Genome Atlas

Glossary

Transesterification

A chemical reaction in which an organic group of an ester (phosphate ester of a nucleotide) is replaced with the alkoxy group of a nucleophilic alcohol (active Tyr residue of a topoisomerase).

Guanosine quadruplexes

Nucleic acid structures in which four guanine bases are connected by hydrogen bonds and form a square planar structure. Such guanine tetrads can pile on top of each other to constitute a guanosine quadruplex.

Ultrafine bridges

(UFBs). A class of mitotic chromatin threads that form bridges linking daughter DNA molecules. UFBs contain DNA and can be stained with antibodies directed against certain helicases but cannot be stained by fluorescent intercalating dyes.

R loops

RNA–DNA hybrids in which a single-stranded RNA hybridizes to a template strand in a DNA duplex and displaces the non-template strand as a loop.

CpG islands

(CGIs). Genomic regions with a high level of CpG dinucleotides.

Pause–release

Regulated pausing and release of RNA polymerase II in promoter-proximal regions, which initiates productive transcription elongation.

Replication origin clusters

Replication origins that tend to fire in coordinated clusters and usually in the same genomic region during S phase.

Replication fork run-off

A consequence of replication fork collision with a TOP1 cleavage complex (TOP1cc) on the leading strand template, resulting in the formation of an irreversible TOP1cc and a DNA double-stranded end.

Catenanes

Topologically interlocked cyclic DNA molecules. Long, linear DNA molecules can approximate these properties and be referred to as catenated, even though this is not formally correct.

Hemicatenanes

A junction of two homologous DNA double helices, in which one strand of a duplex is interlinked with the complementary strand of the other duplex. Unlike catenanes, hemicatenanes can occur in linear DNA molecules.

Fork protection complex

A complex consisting of Timeless, Tipin and other components that stabilizes stalled replication forks and helps to coordinate leading- and lagging-strand synthesis and replication checkpoint signalling.

Endoreduplication

Repeated replication of the nuclear genome in the absence of cell division; it can lead to polyploidy.

D-loop

A DNA structure formed when the two strands are separated and held apart by a third strand that is complementary to one of them. The other strand is displaced and forms a D (DNA) loop.

'Chicken foot' lesions

DNA structures in which newly replicated nascent strands anneal to each other following the retraction of the replication fork. The structure looks like a chicken foot.

Epistatic

A genetic phenomenon in which an observed phenotype depends on the presence of other genes. Epistatic interactions can arise when different genes encode components of a complex or when two genes function in a linear biochemical pathway.

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Pommier, Y., Sun, Y., Huang, Sy. et al. Roles of eukaryotic topoisomerases in transcription, replication and genomic stability. Nat Rev Mol Cell Biol 17, 703–721 (2016). https://doi.org/10.1038/nrm.2016.111

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