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  • Review Article
  • Published:

Mechanisms of DNA replication termination

Nature Reviews Molecular Cell Biology volume 18, pages 507–516 (2017)Cite this article

Subjects

Key Points

  • Termination of DNA replication occurs when two replication forks meet on the same stretch of DNA, during which the following events occur, although not necessarily in this order: forks converge until all intervening DNA is unwound; any remaining gaps are filled and ligated; catenanes are removed; and replication proteins are unloaded.

  • In eukaryotes, most termination sites are determined stochastically by the location of replication initiation sites. In bacteria, termination generally occurs at a specific locus.

  • Replication termination can be a problematic process. Termination of simian virus 40 (SV40) replication involves the stalling of converging forks, and bacterial termination is prone to inducing re-replication. By contrast, fork stalling or re-replication have not been observed during unperturbed termination in eukaryotes.

  • Topological stress accumulates between converging forks and is relieved by the generation of pre-catenanes, which are removed by type II topoisomerases. During bacterial and SV40 termination, type II topoisomerases are required for fork convergence, but in eukaryotes they are dispensable for this purpose.

  • After forks converge, any remaining catenanes are removed by a type II topoisomerase. In eukaryotes, gaps are readily filled by the extension of the leading strands, but in bacteria and SV40 this process is less well-defined.

  • In eukaryotes, a dedicated replisome removal pathway has recently been identified, which operates late during termination, after the DNA is fully replicated. It is unclear whether any comparable pathway exists in bacteria.

Abstract

Genome duplication is carried out by pairs of replication forks that assemble at origins of replication and then move in opposite directions. DNA replication ends when converging replication forks meet. During this process, which is known as replication termination, DNA synthesis is completed, the replication machinery is disassembled and daughter molecules are resolved. In this Review, we outline the steps that are likely to be common to replication termination in most organisms, namely, fork convergence, synthesis completion, replisome disassembly and decatenation. We briefly review the mechanism of termination in the bacterium Escherichia coli and in simian virus 40 (SV40) and also focus on recent advances in eukaryotic replication termination. In particular, we discuss the recently discovered E3 ubiquitin ligases that control replisome disassembly in yeast and higher eukaryotes, and how their activity is regulated to avoid genome instability.

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Figure 1: Steps in DNA replication.
Figure 2: Replication termination in Escherichia coli.
Figure 3: Model for simian virus 40 DNA replication termination.
Figure 4: Model of eukaryotic replication termination.

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Acknowledgements

The authors thank E. Low for critical feedback on the manuscript, and K. Labib and A. Gambus for sharing results before publication. J.C.W.'s work on termination is supported by US National Institutes of Health (NIH) grant GM80676. J.C.W. is an investigator of the Howard Hughes Medical Institute, USA.

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Authors and Affiliations

  1. Department of Biochemistry, Vanderbilt University, Nashville, 37323, Tennessee, USA

    James M. Dewar

  2. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Johannes C. Walter

  3. Department of Biological Chemistry and Molecular Pharmacology, Howard Hughes Medical Institute, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Johannes C. Walter

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Correspondence to Johannes C. Walter.

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PowerPoint slides

Glossary

Origin of DNA replication

(Origin). The location at which replicative helicases are loaded onto DNA, which are generally site-specific in bacteria and yeast, but not in metazoa.

Replication forks

Splayed DNA structures where the replisome is engaged in DNA synthesis.

Topological stress

A structural distortion of the DNA that is caused when the two strands of the double helix are wrapped around each other too many or too few times.

Supercoils

Superhelical twists of the DNA duplex that arise in response to topological stress.

Topoisomerases

Enzymes that relieve topological stress on DNA by cutting and resealing one (type I) or both (type II) DNA strands.

Pre-catenanes

A double-stranded intertwine between two DNA molecules that occurs behind the replication fork, on recently replicated DNA.

Replisomes

The collections of proteins involved in DNA replication at the replication fork.

Fork stalling

A pathological situation in which replication fork progression is impaired.

Okazaki fragment

A short DNA fragment synthesized on the lagging strand template.

Catenane

A double-stranded intertwine between two DNA molecules.

Replicon

A DNA region that is replicated by two replication forks emanating from a single origin.

Replisome progression complex

A large assembly of proteins bound directly or indirectly to the replicative CMG (CDC45–MCM–GINS) helicase.

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Dewar, J., Walter, J. Mechanisms of DNA replication termination. Nat Rev Mol Cell Biol 18, 507–516 (2017). https://doi.org/10.1038/nrm.2017.42

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