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The Role of BRCA1 and BRCA2 in Anticancer Drug Therapy

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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

The genome is under constant assault from both endogenous and exogenous sources such as reactive oxygen species and ionizing radiation capable of inducing a wide array of mutagenic changes [1]. To maintain genomic integrity cells have evolved elegant mechanisms to recognize DNA damage, arrest the cell cycle, and activate specific repair pathways. One of the most cytotoxic lesions that a cell must contend with is a double-strand break (DSB) because even a single unrepaired DSB is capable of inducing cell death [2]. To repair a DSB, cells have at least four mechanisms at their disposal: homologous recombination (HR), single-strand annealing (SSA), nonhomologous end-joining (NHEJ), and microhomology-mediated end joining (MMEJ) (Fig. 1) [3]. HR relies on the sister chromatid as a template to fill in damaged or missing DNA, restoring the chromosome to its original condition. In cells with competent DNA repair mechanisms, HR is the preferred pathway of repair during the S and G2 phase of the cell cycle when the sister chromatid is available [4]. SSA, a variant of HR that is thought to play a minor role in the repair DSBs, utilizes homologous repeats surrounding a DSB to anneal the broken ends resulting in the deletion of the intervening sequence. In contrast, NHEJ and MMEJ both operate throughout the cell cycle and directly ligate two ends of a DSB; however, MMEJ always introduces small deletions at broken ends to produce a region of microhomology to facilitate ligation [5]. The important point to note is that HR is considered an error-free pathway whereas SSA, NHEJ, and MMEJ are error-prone because they can create gross chromosomal aberrations if ligation occurs incorrectly—potentially leading to neoplastic transformation [1].

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Authors and Affiliations

  1. Department of Medical Genetics, McGill University Health Centre, Montreal, QC, Canada, H3G 1A4

    Andrew Y. Shuen & William D. Foulkes

  2. Molecular Pathology Team, The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, SW3 6JB, UK

    Jorge S. Reis-Filho

  3. Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montreal, QC, Canada, H2W 1S6

    William D. Foulkes

  4. Department of Medical Genetics, Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada, H3T 1E2

    William D. Foulkes

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  1. Andrew Y. Shuen
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  2. Jorge S. Reis-Filho
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  3. William D. Foulkes
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Correspondence to William D. Foulkes .

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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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Shuen, A.Y., Reis-Filho, J.S., Foulkes, W.D. (2013). The Role of BRCA1 and BRCA2 in Anticancer Drug Therapy. 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_6

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