Reduced repair capacity of a DNA clustered damage site comprised of 8-oxo-7,8-dihydro-2′-deoxyguanosine and 2-deoxyribonolactone results in an increased mutagenic potential of these lesions

Autor: Peter O'Neill, Siobhan Cunniffe, Martine E. Lomax, Marc M. Greenberg
Rok vydání: 2014
Předmět:
2-Deoxyribonolactone
DNA Repair
Flap Endonucleases
Health
Toxicology and Mutagenesis
DNA polymerase beta
AP
abasic site
chemistry.chemical_compound
0302 clinical medicine
DNA Breaks
Double-Stranded
Flap endonuclease
LP
long patch
chemistry.chemical_classification
0303 health sciences
Escherichia coli Proteins
Base excision repair
SP
short patch
8-Oxo-7
8-dihydro-2′-deoxyguanosine
8-oxodGuo
8-oxo-7
8-dihydro-2′-deoxyguanosine
Biochemistry
8-Hydroxy-2'-Deoxyguanosine
030220 oncology & carcinogenesis
Biological Assay
THF
tetrahydrofuran
Plasmids
DNA repair
Biology
Article
Oxidized abasic sites
03 medical and health sciences
Escherichia coli
Genetics
AP site
Furans
Molecular Biology
DNA Polymerase beta
030304 developmental biology
DNA ligase
Clustered DNA damage
Mutagenesis
Deoxyguanosine
Sugar Acids
Gene Expression Regulation
Bacterial
dL
2-deoxyribonolactone
Molecular biology
chemistry
Gamma Rays
Mutation
Nucleotide excision repair
Zdroj: Mutation Research
ISSN: 0027-5107
DOI: 10.1016/j.mrfmmm.2014.02.005
Popis: Highlights • A dL lesion is not repaired as effectively as an AP site. • The repair of a cluster with dL and 8-oxodGuo lesions is compromised. • Delayed repair of the cluster leads to an increase in mutation frequency.
A signature of ionizing radiation is the induction of DNA clustered damaged sites. Non-double strand break (DSB) clustered damage has been shown to compromise the base excision repair pathway, extending the lifetimes of the lesions within the cluster, compared to isolated lesions. This increases the likelihood the lesions persist to replication and thus increasing the mutagenic potential of the lesions within the cluster. Lesions formed by ionizing radiation include 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodGuo) and 2-deoxyribonolactone (dL). dL poses an additional challenge to the cell as it is not repaired by the short-patch base excision repair pathway. Here we show recalcitrant dL repair is reflected in mutations observed when DNA containing it and a proximal 8-oxodGuo is replicated in Escherichia coli. 8-oxodGuo in close proximity to dL on the opposing DNA strand results in an enhanced frequency of mutation of the lesions within the cluster and a 20 base sequence flanking the clustered damage site in an E. coli based plasmid assay. In vitro repair of a dL lesion is reduced when compared to the repair of an abasic (AP) site and a tetrahydrofuran (THF), and this is due mainly to a reduction in the activity of polymerase β, leading to retarded FEN1 and ligase 1 activities. This study has given insights in to the biological effects of clusters containing dL.
Databáze: OpenAIRE
Externí odkaz: