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Replication stress and cancer

Key Points

  • Replication is a highly regulated process that guarantees the faithful duplication of the genome once per cell cycle, and any condition that compromises it is referred to as replication stress.

  • Replication stress is a major cause of genome instability and is linked to pre-tumour and tumour cells. Several oncogenes cause alterations of replication timing and progression, leading to replication stress.

  • The DNA-damage checkpoint responds to replication stress to guarantee genome stability by protecting stalled forks and promoting replication completion through the activation of dormant replication origins.

  • DNA repair pathways such as homologous recombination restore replication upon DNA breaks that occur at stalled forks.

  • Failures in the cellular response to replication stress, such as those caused by dysfunctions of the DNA-damage checkpoint, replication fork restart or DNA repair, are tumorigenic, as seen in mouse models and human syndromes.

  • Replication stress is not a common feature of normal cells; therefore, it opens up new possibilities for cancer diagnostics and treatment.

Abstract

Genome instability is a hallmark of cancer, and DNA replication is the most vulnerable cellular process that can lead to it. Any condition leading to high levels of DNA damage will result in replication stress, which is a source of genome instability and a feature of pre-cancerous and cancerous cells. Therefore, understanding the molecular basis of replication stress is crucial to the understanding of tumorigenesis. Although a negative aspect of replication stress is its prominent role in tumorigenesis, a positive aspect is that it provides a potential target for cancer therapy. In this Review, we discuss the link between persistent replication stress and tumorigenesis, with the goal of shedding light on the mechanisms underlying the initiation of an oncogenic process, which should open up new possibilities for cancer diagnostics and treatment.

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Figure 1: Oncogene-induced replication stress.
Figure 2: Replication impairment activates the checkpoint.
Figure 3: Impaired replication fork progression.
Figure 4: Genomic instability resulting from replication stress.

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Acknowledgements

The authors would like to thank O. Fernandez-Capetillo and P. Huertas for their 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 PharmaMar. The authors apologize to those whose work could not be cited owing to space limitations.

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Glossary

Senescence

A sustained growth arrest in which cells are refractory to mitogen stimulation and apoptosis.

Replication fork

DNA region at which unwinding of the double helix and synthesis of the complementary strands occur.

S phase checkpoints

The quality-control mechanisms that guarantee genome integrity during DNA replication.

Replisome

A protein complex involved in DNA replication that moves along the DNA as the nascent complementary strands are synthesized.

Seckel syndrome

A rare autosomal recessive disorder, due to mutations in the ATR gene, which is characterized by intrauterine growth retardation, dwarfism, microcephaly with severe mental retardation and a bird-headed facial appearance.

Hypomorphic mice

Transgenic mice carrying a mutation that causes a partial decrease in the activity of the affected gene.

Replication intermediates

DNA structures formed transiently during the process of replication.

DNA primase

Enzyme that catalyses the synthesis of a short RNA segment called a primer that is needed by DNA polymerases to start DNA synthesis.

Replication fork collisions

Physical encounters between an advancing replication fork and another on-going process, such as transcription, taking place on the same DNA molecule.

Non-B DNA structures

Secondary DNA structures that are different from right-handed double helical B DNA structures.

Reversed forks

DNA structures that are formed when the nascent leading strand hybridizes to the corresponding lagging strand at a replication fork.

Telangiectasias

Small dilated blood vessels in the outer layer of the skin.

Homologous recombination

(HR). Error-free double-strand break repair pathway that involves identical or homologous DNA sequences as templates.

Non-homologous end joining

(NHEJ). Error-prone double-strand break repair pathway that directly ligates DNA ends.

Loss of heterozygosity

(LOH). Loss of the wild-type allele of a diploid cell by deletion, gene conversion or chromosome loss.

Nondisjunction

Lack of chromosome segregation that gives rise to daughter cells with an abnormal number of chromosomes.

Anaphase bridges

String-like DNA fibres connecting two nuclei during chromosome segregation due to unresolved recombination or replication intermediates.

Breakage–fusion–bridge

Cycles of chromosome truncation and rescue by fusion of replicated sister chromatids resulting in chromosome rearrangements.

Cleavage furrow

Infolding of the cell membrane at the equatorial plane of the cell occurring during cytokinesis.

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Gaillard, H., García-Muse, T. & Aguilera, A. Replication stress and cancer. Nat Rev Cancer 15, 276–289 (2015). https://doi.org/10.1038/nrc3916

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