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  • Review Article
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DNA damage and the balance between survival and death in cancer biology

Nature Reviews Cancer volume 16, pages 20–33 (2016)Cite this article

Subjects

Key Points

  • The constant deleterious modification of DNA by reactive molecules, endogenously or exogenously generated, is offset by protective processes that are initiated by the DNA damage response.

  • The interplay of the diverse signalling cascades (DNA damage response) that originate from the interference of DNA lesions with replication and the transcriptome leads to the activation of DNA repair, autophagy, senescence, apoptosis and necroptosis.

  • Aspects of how post-translational modifications of the tumour suppressor p53 determine the switch between these end points are discussed.

  • The crosstalk between autophagy, senescence, apoptosis and regulated necrosis is also discussed, focusing on the importance of thresholds for deciding cell fate.

  • Throughout this Review, emphasis is placed on how DNA damage and DNA repair fit within the complex cellular context.

Abstract

DNA is vulnerable to damage resulting from endogenous metabolites, environmental and dietary carcinogens, some anti-inflammatory drugs, and genotoxic cancer therapeutics. Cells respond to DNA damage by activating complex signalling networks that decide cell fate, promoting not only DNA repair and survival but also cell death. The decision between cell survival and death following DNA damage rests on factors that are involved in DNA damage recognition, and DNA repair and damage tolerance, as well as on factors involved in the activation of apoptosis, necrosis, autophagy and senescence. The pathways that dictate cell fate are entwined and have key roles in cancer initiation and progression. Furthermore, they determine the outcome of cancer therapy with genotoxic drugs. Understanding the molecular basis of these pathways is important not only for gaining insight into carcinogenesis, but also in promoting successful cancer therapy. In this Review, we describe key decision-making nodes in the complex interplay between cell survival and death following DNA damage.

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Figure 1: Cellular consequences of DNA damage.
Figure 2: DNA damage-dependent apoptosis.
Figure 3: The DNA damage response activates both pro-survival and pro-death signalling.
Figure 4: DNA damage-dependent senescence.
Figure 5: DNA damage-dependent autophagy.

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Acknowledgements

The authors' work is supported by Deutsche Forschungsgemeinschaft (DFG KA724 and RO3617) and Deutsche Krebshilfe.

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  1. Institute of Toxicology, University Medical Center, Obere Zahlbacher Strasse 67, D-55131, Mainz, Germany

    Wynand P. Roos, Adam D. Thomas & Bernd Kaina

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Supplementary information

41568_2016_BFnrc20152_MOESM179_ESM.pdf

Supplementary information S1 (table) | A non-exhaustive list of clinically relevant strategies for targeting key enzymes in the pro-survival pathways, activated following DNA damage and some examples of their effects and stages of clinical assessment. (PDF 177 kb)

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Glossary

Ataxia telangiectasia

A heritable disorder caused by mutated ATM. Patients suffering from this disease are predisposed to cancer and are very sensitive to ionizing radiation.

Necroptosis

A form of regulated necrosis that the cell uses when apoptosis cannot be initiated. During necroptosis the content of the cell is released into the extracellular space and causes inflammation.

Ferroptosis

A regulated, non-apoptotic form of cell death that is dependent on iron.

PML bodies

Heterogeneous nuclear structures that range in size from 0.2 to 1 micrometre. They are found in most mammalian cell nuclei and have been ascribed functions in tumour suppression and transcription regulation, among others.

End-to-end fusion

The ends of linear DNA are protected by telomeres. When double-strand breaks (DSBs) occur in telomeres and telomeres are partially lost, DSB repair can fuse two broken telomeric ends. This can be seen in mitosis as two chromosomes connected at their ends.

Jasplakinolide

A drug originally isolated from a sponge used for the stabilization and polymerization of the actin filament. It triggers apoptosis in a DNA damage-independent manner.

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Roos, W., Thomas, A. & Kaina, B. DNA damage and the balance between survival and death in cancer biology. Nat Rev Cancer 16, 20–33 (2016). https://doi.org/10.1038/nrc.2015.2

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