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Control of DNA Replication by ATR

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Targeting the DNA Damage Response for Anti-Cancer Therapy

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

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Abstract

DNA replication needs to be carefully controlled to prevent genomic instability and ensure cellular fitness. ATR is a PI3K-like kinase and is a central factor supervising the correct completion of DNA replication. The recruitment, activation and specific substrate recognition of ATR is tightly regulated to promote differential responses at a local (fork), regional (replication factory) and global (nucleus) level. Both during normal S phase or in response to the stalling of replication forks, ATR is responsible for fork stabilization and repair, as well as checkpoint activation together with its substrate, the CHK1 kinase. Malignant transformation is accompanied by oncogenic mutations that promote unscheduled entry into S phase and an increase in problems during DNA replication. This renders cancer cells particularly dependent on a proficient replication stress response for their survival, making the ATR-CHK1 pathway an attractive target for cancer treatment. In this chapter, we review the mechanisms of ATR activation, its downstream effects, and the functions of this pathway in cancer.

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Authors and Affiliations

  1. Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), Madrid, 28029, Spain

    Emilio Lecona & Oscar Fernández-Capetillo

  2. Science for Life Laboratory, Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, S-171 21, Stockholm, Sweden

    Oscar Fernández-Capetillo

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  1. Emilio Lecona
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Correspondence to Oscar Fernández-Capetillo .

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  1. Vertex Pharmaceuticals (Europe) Ltd, Abingdon, Oxfordshire, United Kingdom

    John Pollard

  2. Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom

    Nicola Curtin

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Lecona, E., Fernández-Capetillo, O. (2018). Control of DNA Replication by ATR. In: Pollard, J., Curtin, N. (eds) Targeting the DNA Damage Response for Anti-Cancer Therapy. Cancer Drug Discovery and Development. Humana Press, Cham. https://doi.org/10.1007/978-3-319-75836-7_3

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