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ATR as a Therapeutic Target

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Advances in DNA Repair in Cancer Therapy

Part of the book series: Cancer Drug Discovery and Development ((CDD&D,volume 72))

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Abstract

Ataxia Telangiectasia Mutated and Rad3-related (ATR) is a vital sensor of a variety of DNA lesions and is critical to cell cycle arrest at the S and G2 checkpoints as well as initiation of DNA repair via homologous recombination repair (HRR). ATR is a member of the PI-3K like family of kinases (PIKKs), which include Ataxia Telangiectasia Mutated (ATM) and DNA-PKCS(DNA-dependent protein kinase catalytic subunit) [1]; protein kinases that are also involved in the complex network of DNA damage signalling and repair mechanisms known as the DNA damage response (DDR). The DDR comprises sensor proteins which detect the DNA damage and signal to transducer proteins, e.g. p53 and checkpoint kinases which then transmit this information to downstream effector proteins. These effectors activate the appropriate damage response, be it cell cycle arrest and DNA repair or apoptosis. Many of the phosphorylation substrates of ATR are also common to ATM, and the two are both involved in HRR in response to double strand breaks (DSBs). There is also crosstalk between the two PIKKs. ATM and ATR phosphorylate >900 sites on >700 proteins in response to DNA damage induced, experimentally, highlighting the complexity of the network. The majority of phosphorylated proteins are involved in DNA replication, recombination and repair plus cell cycle regulation [2].

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Authors and Affiliations

  1. Northern Institute for Cancer Research, Newcastle University, Paul O’Gorman Building, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK

    Fiona K. Middleton & Nicola J. Curtin

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  1. Fiona K. Middleton
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  2. Nicola J. Curtin
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Correspondence to Nicola J. Curtin .

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  1. Jewish General Hospital, 3755 Cote Ste. Catherine Road, Montreal, H3T 1E2, Canada

    Lawrence Panasci

  2. , Department of Oncology, McGill University, 3755 Côte Ste-Catherine Road, Montreal, H3T 1E2, Canada

    Raquel Aloyz

  3. McGill University, Department of Medicine and Oncology, Faculty of Medicine, 3755 Côte Ste-Catherine Road, Montreal, H3T 1E2, Canada

    Moulay Alaoui-Jamali

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Middleton, F.K., Curtin, N.J. (2013). ATR as a Therapeutic Target. In: Panasci, L., Aloyz, R., Alaoui-Jamali, M. (eds) Advances in DNA Repair in Cancer Therapy. Cancer Drug Discovery and Development, vol 72. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-4741-2_10

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