BRCA2-dependent homologous recombination is required for repair of Arsenite-induced replication lesions in mammalian cells
| Autor: | Thomas Helleday, Sarah Bottomley, Songmin Ying, Helen E. Bryant, Katie N. Myers |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
DNA Replication
DNA Repair Arsenites DNA repair Genome Integrity Repair and Replication Biology medicine.disease_cause Cell Line chemistry.chemical_compound Cricetulus Cricetinae Genetics medicine Animals DNA Breaks Double-Stranded Carcinogen Arsenite BRCA2 Protein Recombination Genetic Mutation DNA replication DNA Replication Fork Molecular biology chemistry Carcinogens Homologous recombination DNA |
| Zdroj: | Nucleic Acids Research |
| ISSN: | 1362-4962 0305-1048 |
| Popis: | Arsenic exposure constitutes one of the most\ud widespread environmental carcinogens, and is\ud associated with increased risk of many different\ud types of cancers. Here we report that arsenite\ud (As[III]) can induce both replication-dependent\ud DNA double-strand breaks (DSB) and homologous\ud recombination (HR) at doses as low as 5 mM\ud (0.65 mg/l), which are within the typical doses often\ud found in drinking water in contaminated areas.\ud We show that the production of DSBs is dependent\ud on active replication and is likely to be the result\ud of conversion of a DNA single-strand break (SSB)\ud into a toxic DSB when encountered by a replication\ud fork. We demonstrate that HR is required for the\ud repair of these breaks and show that a functional\ud HR pathway protects against As[III]-induced cytotoxicity.\ud In addition, BRCA2-deficient cells are sensitive\ud to As[III] and we suggest that As[III] could be\ud exploited as a therapy for HR-deficient tumours\ud such as BRCA1 and BRCA2 mutated breast and\ud ovarian cancers. |
| Databáze: | OpenAIRE |
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