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Reduced ligation during DNA base excision repair supported by BRCA2 mutant cells

Oncogene volume 19, pages 5781–5787 (2000)Cite this article

Abstract

The brest cancer predisposing genes BRCA1 and BRCA2 appear to be involved in DNA repair. In particular, the sensitivity of BRCA2-deficient mouse embryonic fibroblasts to ionizing radiation and the demonstrated interaction of the BRCA2 protein with Rad51, a major factor in recombinational repair, indicate that BRCA2 is important for double strand break repair. The human BRCA2-deficient human cell line Capan-1, whilst being sensitive to ionizing radiation, is also sensitive to the alkylating agent methymethanesulfonate. The major lesions induced by this agent are methylated bases which are removed primarily by the base excision repair (BER) pathway. We have investigated the efficiency of BER in Capan-1 cells by an in vitro assay in which plasmid substrates containing a single lesion are repaired by mammalian cell extracts. In comparison to the control cell lines BxPC-3, T24 and MCF7, Capan-1 cells exhibited a reduced rate of DNA ligation during both the single-nucleotide insertion and PCNA-dependent pathways of BER. The reduced rate of DNA ligation exhibited by Capan-1 cell extracts was complemented by addition of bacteriophage T4 DNA ligase or human DNA ligase III. BRCA2-mutant Capan-1 cells may possess reduced DNA ligase activity during BER.

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Acknowledgements

This work was partially supported by Telethon Italy, Italian Association for Cancer Research (AIRC), National Research Council [grant no. 99.02487.CT04 (*)] and Italian Ministry of Health. M Bogliolo was the recipient of an Italian Foundation for Cancer Research fellowship.

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Authors and Affiliations

  1. DNA Repair Unit, Mutagenesis Laboratory–Istituto Nazionale Ricerca Cancro, Largo Rosanna Benzi n. 10, Genova, 16132, Italy

    Massimo Bogliolo & Guido Frosina

  2. AstraZeneca Laboratory for Cell and Molecular Biology, School of Biological Sciences, University of Manchester, Manchester, M13 9PT, UK

    Richard M Taylor & Keith W Caldecott

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  1. Massimo Bogliolo
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Bogliolo, M., Taylor, R., Caldecott, K. et al. Reduced ligation during DNA base excision repair supported by BRCA2 mutant cells. Oncogene 19, 5781–5787 (2000). https://doi.org/10.1038/sj.onc.1203951

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