title: Oxidized dNTPs and the OGG1 and MUTYH DNA glycosylases combine to induce CAG/CTG repeat instability.
abstract: DNA trinucleotide repeat (TNR) expansion underlies several neurodegenerative disorders including Huntington's disease (HD). Accumulation of oxidized DNA bases and their inefficient processing by base excision repair (BER) are among the factors suggested to contribute to TNR expansion. In this study, we have examined whether oxidation of the purine dNTPs in the dNTP pool provides a source of DNA damage that promotes TNR expansion. We demonstrate that during BER of 8-oxoguanine (8-oxodG) in TNR sequences, DNA polymerase β (POL β) can incorporate 8-oxodGMP with the formation of 8-oxodG:C and 8-oxodG:A mispairs. Their processing by the OGG1 and MUTYH DNA glycosylases generates closely spaced incisions on opposite DNA strands that are permissive for TNR expansion. Evidence in HD model R6/2 mice indicates that these DNA glycosylases are present in brain areas affected by neurodegeneration. Consistent with prevailing oxidative stress, the same brain areas contained increased DNA 8-oxodG levels and expression of the p53-inducible ribonucleotide reductase. Our in vitro and in vivo data support a model where an oxidized dNTPs pool together with aberrant BER processing contribute to TNR expansion in non-replicating cells.
authors.affiliation: Department of Environment and Primary Prevention, Istituto Superiore di Sanità, 00161 Roma, Italy Department of Science, University Roma Tre, 00154 Roma, Italy.
authors.forename: Piera
authors.initials: P
authors.lastname: Cilli
authors.affiliation: Department of Environment and Primary Prevention, Istituto Superiore di Sanità, 00161 Roma, Italy.
authors.forename: Ilenia
authors.initials: I
authors.lastname: Ventura
authors.affiliation: Department of Environment and Primary Prevention, Istituto Superiore di Sanità, 00161 Roma, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Minoprio
authors.affiliation: Department of Environment and Primary Prevention, Istituto Superiore di Sanità, 00161 Roma, Italy.
authors.forename: Ettore
authors.initials: E
authors.lastname: Meccia
authors.affiliation: Department of Drug Safety and Evaluation, Istituto Superiore di Sanità, 00161 Roma, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Martire
authors.affiliation: Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
authors.forename: Samuel H
authors.initials: SH
authors.lastname: Wilson
authors.affiliation: Department of Environment and Primary Prevention, Istituto Superiore di Sanità, 00161 Roma, Italy Margherita.bignami@gmail.com.
authors.forename: Margherita
authors.initials: M
authors.lastname: Bignami
authors.affiliation: Department of Environment and Primary Prevention, Istituto Superiore di Sanità, 00161 Roma, Italy filomena.mazzei@iss.it.
authors.forename: Filomena
authors.initials: F
authors.lastname: Mazzei
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D004247:DNA / Q000235:genetics* / Q000378:metabolism*; D045647:DNA Glycosylases / Q000378:metabolism*; D019951:DNA Polymerase beta / Q000378:metabolism; D004260:DNA Repair; D003849:Deoxyguanosine / Q000031:analogs & derivatives; D005260:Female; D042822:Genomic Instability; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D019680:Trinucleotide Repeat Expansion; D018911:Trinucleotide Repeats
chemical_list: D000080242:8-Hydroxy-2'-Deoxyguanosine; D004247:DNA; D019951:DNA Polymerase beta; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase; C479058:oxoguanine glycosylase 1, human; D003849:Deoxyguanosine