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Transcription–replication conflicts: how they occur and how they are resolved

Nature Reviews Molecular Cell Biology volume 17, pages 553–563 (2016)Cite this article

Subjects

Key Points

  • Transcription and replication occur at high frequency in cells. As they share the same DNA template, a high incidence of encounters is expected between the transcription and replication machineries, which can cause transcription–replication conflicts, DNA damage and genomic instability.

  • Cells have developed different strategies to reduce or prevent transcription–replication encounters, from genome organization favouring co-orientation of replication and transcription to specific mechanisms to avoid or resolve such collisions.

  • Transcription–replication collisions can occur owing to cis structural features, such as changes in DNA supercoiling, or secondary DNA structures, including hairpins, G-quadruplexes and RNA–DNA hybrids, which have the capacity to hinder replication fork progression.

  • The factors that minimize collisions include the transcription machinery itself and mRNA-processing proteins, as well as factors that help or facilitate replication progression, such as DNA helicases and topoisomerases or chromatin-remodelling complexes.

  • The DNA damage response is able to sense a stalled replication fork caused by transcription–replication conflicts and to promote various mechanisms that solve the collisions. This includes, for example, the removal of the RNA polymerase and the action of various repair pathways, such as the Fanconi anaemia pathway.

  • A better understanding of the dynamics of replication and transcription machineries will help to clarify the importance of transcription–replication collisions as a source of genomic instability and to open up the possibility of using them as selective targets in cancer therapy.

Abstract

The frequent occurrence of transcription and DNA replication in cells results in many encounters, and thus conflicts, between the transcription and replication machineries. These conflicts constitute a major intrinsic source of genome instability, which is a hallmark of cancer cells. How the replication machinery progresses along a DNA molecule occupied by an RNA polymerase is an old question. Here we review recent data on the biological relevance of transcription–replication conflicts, and the factors and mechanisms that are involved in either preventing or resolving them, mainly in eukaryotes. On the basis of these data, we provide our current view of how transcription can generate obstacles to replication, including torsional stress and non-B DNA structures, and of the different cellular processes that have evolved to solve them.

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Figure 1: Transcription and replication.
Figure 2: Head-on and co-directional transcription–replication collisions.
Figure 3: Conditions that affect the occurrence of transcription–replication collisions.
Figure 4: Mechanisms preventing transcription–replication collisions.
Figure 5: Resolving transcription–replication collisions to avoid genome instability.

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Acknowledgements

The authors thank B. Gómez-González for her comments on the manuscript and D. Haun for style supervision. Research in A.A.'s laboratory is funded by grants from the Spanish Ministry of Economy and Competitiveness, the Junta de Andalucía, the European Union (FEDER), Worldwide Cancer Research and the European Research Council. The authors apologize to those whose work could not be cited owing to space limitations.

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  1. Centro Andaluz de Biología Molecular y Medicina Regenerativa-CABIMER, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Seville, 41092, Spain

    Tatiana García-Muse & Andrés Aguilera

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  1. Tatiana García-Muse
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  2. Andrés Aguilera
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Correspondence to Andrés Aguilera.

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PowerPoint slides

Glossary

Transcription-coupled repair

Subpathway of the nucleotide excision repair pathway that removes lesions from the template DNA strands at actively transcribed genes.

Torsional stress

Physical stress at the DNA molecule generated by over-rotation of the double helix; manifested as the accumulation of positive or negative supercoils.

Non-B DNA

Any DNA structure that is different from right-handed double helix with 10 nucleotides per turn.

Replisomes

Protein complexes with helicase, primase and DNA polymerase activities that conduct DNA replication.

Supercoiling

Over- or under-winding of the DNA helix.

Hairpins

DNA structures in which a strand folds on itself and forms intrastrand base pairing.

Triplex DNA

A single-stranded DNA region bound to the major groove of the DNA duplex forming a three-stranded helix, normally at sequences with mirror symmetry.

G-quadruplexes

Four repeats of at least three guanines that can interact to form four-stranded DNA structures.

DNA combing

A method for the analysis of single DNA molecules; it is used for studying DNA replication.

γH2AX foci

A histone H2A variant that is phosphorylated (γH2AX) and forms nuclear foci, which are generally accepted as markers of DNA double-strand breaks.

CpG islands

Chromosomal regions with a high density of non-methylated CpG sequences, which are often located at gene promoters.

Break-seq

A technique to map chromosome breaks based on DNA double-strand break labelling and next-generation sequencing.

Bromodeoxyuridine

A synthetic analogue of the thymidine nucleoside; it is used to follow DNA synthesis.

RecQ family

DNA helicase proteins characterized by their helicase domain, which is essential for ATP binding and hydrolysis, and the RecQ domain, which is required for DNA binding.

DNA damage response

(DDR). A network of DNA damage repair and checkpoint factors that function together to repair DNA lesions.

Phosphomimetic

Proteins with amino acid substitutions that simulate their phosphorylated state.

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García-Muse, T., Aguilera, A. Transcription–replication conflicts: how they occur and how they are resolved. Nat Rev Mol Cell Biol 17, 553–563 (2016). https://doi.org/10.1038/nrm.2016.88

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