title: Aberrant repair initiated by mismatch-specific thymine-DNA glycosylases provides a mechanism for the mutational bias observed in CpG islands.
abstract: The human thymine-DNA glycosylase (TDG) initiates the base excision repair (BER) pathway to remove spontaneous and induced DNA base damage. It was first biochemically characterized for its ability to remove T mispaired with G in CpG context. TDG is involved in the epigenetic regulation of gene expressions by protecting CpG-rich promoters from de novo DNA methylation. Here we demonstrate that TDG initiates aberrant repair by excising T when it is paired with a damaged adenine residue in DNA duplex. TDG targets the non-damaged DNA strand and efficiently excises T opposite of hypoxanthine (Hx), 1,N(6)-ethenoadenine, 7,8-dihydro-8-oxoadenine and abasic site in TpG/CpX context, where X is a modified residue. In vitro reconstitution of BER with duplex DNA containing Hx•T pair and TDG results in incorporation of cytosine across Hx. Furthermore, analysis of the mutation spectra inferred from single nucleotide polymorphisms in human population revealed a highly biased mutation pattern within CpG islands (CGIs), with enhanced mutation rate at CpA and TpG sites. These findings demonstrate that under experimental conditions used TDG catalyzes sequence context-dependent aberrant removal of thymine, which results in TpG, CpA→CpG mutations, thus providing a plausible mechanism for the putative evolutionary origin of the CGIs in mammalian genomes.
authors.affiliation: Groupe Réparation de l'ADN, Université Paris Sud, Laboratoire Stabilité Génétique et Oncogenèse CNRS, UMR 8200, Gustave Roussy, F-94805 Villejuif Cedex, France.
authors.forename: Ibtissam
authors.initials: I
authors.lastname: Talhaoui
authors.affiliation: Laboratoire de Génétique Oncologique EPHE, INSERM U753, Gustave Roussy, F-94805 Villejuif, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Couve
authors.affiliation: Groupe Réparation de l'ADN, Université Paris Sud, Laboratoire Stabilité Génétique et Oncogenèse CNRS, UMR 8200, Gustave Roussy, F-94805 Villejuif Cedex, France AB Science SA, 75008 Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Gros
authors.affiliation: Groupe Réparation de l'ADN, Université Paris Sud, Laboratoire Stabilité Génétique et Oncogenèse CNRS, UMR 8200, Gustave Roussy, F-94805 Villejuif Cedex, France.
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Ishchenko
authors.affiliation: Nazarbayev University Research and Innovation System, Astana 010000, Kazakhstan.
authors.forename: Bakhyt
authors.initials: B
authors.lastname: Matkarimov
authors.affiliation: Groupe Réparation de l'ADN, Université Paris Sud, Laboratoire Stabilité Génétique et Oncogenèse CNRS, UMR 8200, Gustave Roussy, F-94805 Villejuif Cedex, France murat.saparbaev@gustaveroussy.fr.
authors.forename: Murat K
authors.initials: MK
authors.lastname: Saparbaev
mesh_terms: D000225:Adenine / Q000737:chemistry; D000818:Animals; D020137:Base Pair Mismatch; D002478:Cells, Cultured; D018899:CpG Islands; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D006801:Humans; D051379:Mice; D009154:Mutation; D009841:Oligonucleotides / Q000737:chemistry; D020641:Polymorphism, Single Nucleotide; D013941:Thymine / Q000737:chemistry / Q000378:metabolism; D044502:Thymine DNA Glycosylase / Q000378:metabolism*
chemical_list: D009841:Oligonucleotides; D004247:DNA; D044502:Thymine DNA Glycosylase; D000225:Adenine; D013941:Thymine