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The plasticity of DNA replication forks in response to clinically relevant genotoxic stress

Nature Reviews Molecular Cell Biology volume 21, pages 633–651 (2020)Cite this article

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Abstract

Complete and accurate DNA replication requires the progression of replication forks through DNA damage, actively transcribed regions, structured DNA and compact chromatin. Recent studies have revealed a remarkable plasticity of the replication process in dealing with these obstacles, which includes modulation of replication origin firing, of the architecture of replication forks, and of the functional organization of the replication machinery in response to replication stress. However, these specialized mechanisms also expose cells to potentially dangerous transactions while replicating DNA. In this Review, we discuss how replication forks are actively stalled, remodelled, processed, protected and restarted in response to specific types of stress. We also discuss adaptations of the replication machinery and the role of chromatin modifications during these transactions. Finally, we discuss interesting recent data on the relevance of replication fork plasticity to human health, covering its role in tumorigenesis, its crosstalk with innate immunity responses and its potential as an effective cancer therapy target.

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Fig. 1: Overview of the mechanisms underlying replication fork plasticity.
Fig. 2: Replication fork remodelling and restart during replication stress.
Fig. 3: Nucleolytic processing and restart of stalled replication forks.
Fig. 4: Replisome plasticity under replication stress.
Fig. 5: Crosstalk between replication fork protection and chromatin modification.
Fig. 6: DNA replication and repair can generate cytoplasmic DNA that activates an innate immunity response.

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Acknowledgements

The authors apologize to all those researchers whose relevant work could not be cited because of space limitations. This work was supported by a Marie Skłodowska-Curie Fellowship (704817) to M.B., by a US National Institutes of Health grant (R01GM116616) to D.C., and by grants from the Swiss National Science Foundation (31003A_169959 and 310030_189206), Swiss Cancer League (KFS-3967-08-2016) and European Research Council (Consolidator Grant 617102) to M.L.

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  1. Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland

    Matteo Berti & Massimo Lopes

  2. Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA

    David Cortez

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Supplementary information

Glossary

Repriming

Synthesis of short RNA sequences required for the restart of DNA synthesis after transient DNA polymerase blocking.

Replisome

A large protein complex that carries out DNA replication through its multiple enzymatic activities and that includes helicase, primase and DNA polymerases.

Fork uncoupling

Here, mainly used to describe uncoupling between helicase translocation and interrupted leading-strand polymerization.

Fork reversal

Conversion of standard three-way replication forks into four-way junctions, via re-annealing of the unwound parental duplex, followed by backtracking of the replication fork and annealing of the newly synthesized strands.

Template switching

DNA-damage tolerance pathway based on the use of a newly synthesized strand as an alternative template for DNA synthesis when the parental DNA is damaged.

Branch migration

Consecutive exchange of base pairings on homologous DNA strands at reversed forks or Holliday junctions, which moves the branch point up or down the DNA sequence.

Primase activity

Synthesis of short RNA sequences that are required for priming the activity of DNA polymerases.

MCM2–5 gate

An interface between the eponymous subunits of the MCM helicase. Opening of the gate is required in order to transition the helicase from dsDNA binding at replication origins to encircling the ssDNA template for leading-strand synthesis.

Lock–washer conformation

A transiently open conformation of the MCM helicase that allows the transition from dsDNA binding to ssDNA binding during the activation of DNA synthesis at replication origins.

Topologically associated domains

A 3D genome organization feature identified by chromosome conformation capture techniques, referring to genomic regions in which DNA sequences preferentially interact with each other rather than with other genomic sequences.

Microsatellite instability-high cancers

Tumours (typically arising in the colon) that display genetic hypermutability, usually owing to impaired DNA mismatch repair.

Anti-PD-1 therapy

Cancer treatment using drugs that block the interaction of specific cancer ligands with the immune checkpoint receptor PD-1 present on the surface of T cells, thereby preventing cancer cell evasion from the immune system.

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Berti, M., Cortez, D. & Lopes, M. The plasticity of DNA replication forks in response to clinically relevant genotoxic stress. Nat Rev Mol Cell Biol 21, 633–651 (2020). https://doi.org/10.1038/s41580-020-0257-5

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