TY - JOUR
T1 - Aberrant repair initiated by mismatch-specific thymine-DNA glycosylases provides a mechanism for the mutational bias observed in CpG islands
AU - Talhaoui, Ibtissam
AU - Couve, Sophie
AU - Gros, Laurent
AU - Ishchenko, Alexander A.
AU - Matkarimov, Bakhyt
AU - Saparbaev, Murat K.
N1 - Funding Information:
Agence Nationale pour la Recherche [ANR Blanc 2010 Projet ANR-10-BLAN-1617 to M.K.S.]; Fondation pour la Recherche Médicale [EQUIPES FRM 2007 DEQ20071210556 to M.K.S.]; Electricité de France [RB 2014-26 to M.K.S.]; Fondation de France [#2012 00029161 to A.A.I.]; Science Committee of the Ministry of Education and Science of the Republic of Kazakhstan to B.M.; I.T, S.C. and L.G. were supported by postdoctoral fellowships funded by the grants from Fondation ARC [PDF20110603195], FRM [DEQ20071210556] and European Community [FP6 Euroatom Grant RISC-RAD FI6R-CT-2003-508842], respectively. Funding for open access charge: Grant from Nazarbayev University Research and Innovation System [RB 2014-26]. Conflict of interest statement. None declared.
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
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U2 - 10.1093/nar/gku246
DO - 10.1093/nar/gku246
M3 - Article
C2 - 24692658
AN - SCOPUS:84903200325
VL - 42
SP - 6300
EP - 6313
JO - Nucleic Acids Research
JF - Nucleic Acids Research
SN - 0305-1048
IS - 10
ER -