Processing of thymine glycol in a clustered DNA damage site: mutagenic or cytotoxic
Autor: | Peter O’Neill, Naoya Shikazono, Sophie Bellon, Martine Lomax, Siobhan Cunniffe |
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Jazyk: | angličtina |
Rok vydání: | 2009 |
Předmět: |
DNA Repair
DNA damage DNA repair Biology Genome Integrity Repair and Replication Endonuclease chemistry.chemical_compound Genetics Escherichia coli AP site heterocyclic compounds DNA Breaks Double-Stranded DNA Breaks Single-Stranded Uracil Mutagenesis Deoxyguanosine Base excision repair Molecular biology Thymine Biochemistry chemistry 8-Hydroxy-2'-Deoxyguanosine biology.protein Transformation Bacterial DNA DNA Damage |
Zdroj: | Nucleic Acids Research |
ISSN: | 1362-4962 0305-1048 |
Popis: | Localized clustering of damage is a hallmark of certain DNA-damaging agents, particularly ionizing radiation. The potential for genetic change arising from the effects of clustered damage sites containing combinations of AP sites, 8-oxo-7,8-dihydroguanine (8-oxoG) or 5,6-dihydrothymine is high. To date clusters containing a DNA base lesion that is a strong block to replicative polymerases, have not been explored. Since thymine glycol (Tg) is non-mutagenic but a strong block to replicative polymerases, we have investigated whether clusters containing Tg are highly mutagenic or lead to potentially cytotoxic lesions, when closely opposed to either 8-oxoG or an AP site. Using a bacterial plasmid-based assay and repair assays using cell extracts or purified proteins, we have shown that DNA double-strand breaks (DSBs) arise when Tg is opposite to an AP site, either through attempted base excision repair or at replication. In contrast, 8-oxoG opposite to Tg in a cluster 'protects' against DSB formation but does enhance the mutation frequency at the site of 8-oxoG relative to that at a single 8-oxoG, due to the decisive role of endonucleases in the initial stages of processing Tg/8-oxoG clusters, removing Tg to give an intermediate with an abasic site or single-strand break. |
Databáze: | OpenAIRE |
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