Ying, S.M., Myers, K., Bottomley, S. et al. (2 more authors) (2009) BRCA2-dependent homologous recombination is required for repair of Arsenite-induced replication lesions in mammalian cells. Nucleic Acids Research, 37 (15). pp. 5105-5113. ISSN 0305-1048
Abstract
Arsenic exposure constitutes one of the most widespread environmental carcinogens, and is associated with increased risk of many different types of cancers. Here we report that arsenite (As[III]) can induce both replication-dependent DNA double-strand breaks (DSB) and homologous recombination (HR) at doses as low as 5 mM (0.65 mg/l), which are within the typical doses often found in drinking water in contaminated areas. We show that the production of DSBs is dependent on active replication and is likely to be the result of conversion of a DNA single-strand break (SSB) into a toxic DSB when encountered by a replication fork. We demonstrate that HR is required for the repair of these breaks and show that a functional HR pathway protects against As[III]-induced cytotoxicity. In addition, BRCA2-deficient cells are sensitive to As[III] and we suggest that As[III] could be exploited as a therapy for HR-deficient tumours such as BRCA1 and BRCA2 mutated breast and ovarian cancers.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2009 The Author(s) This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. |
Keywords: | OXIDATIVE DNA-DAMAGE; DOUBLE-STRAND BREAKS; PROTEIN CROSS-LINKS; SISTER-CHROMATID EXCHANGE; CULTURED HUMAN-CELLS; DRINKING-WATER; GENE-EXPRESSION; POLY(ADP-RIBOSE) POLYMERASE; CHROMOSOMAL INSTABILITY; METHYLATED METABOLITES |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > The Medical School (Sheffield) > Division of Genomic Medicine (Sheffield) > Department of Oncology and Metabolism (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 02 May 2017 13:44 |
Last Modified: | 02 May 2017 13:44 |
Published Version: | http://doi.org/10.1093/nar/gkp538 |
Status: | Published |
Publisher: | Oxford University Press |
Refereed: | Yes |
Identification Number: | 10.1093/nar/gkp538 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:115358 |