期刊
NUCLEIC ACIDS RESEARCH
卷 42, 期 10, 页码 6300-6313出版社
OXFORD UNIV PRESS
DOI: 10.1093/nar/gku246
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资金
- Agence Nationale pour la Recherche [ANR Blanc Projet] [ANR-10-BLAN-1617]
- Fondation pour la Recherche Medicale [EQUIPES FRM DEQ20071210556]
- Electricite de France [RB 2014-26]
- Fondation de France [2012 00029161]
- Science Committee of the Ministry of Education and Science of the Republic of Kazakhstan
- Fondation ARC [PDF20110603195]
- FRM [DEQ20071210556]
- European Community [RISC-RAD FI6R-CT-2003-508842]
- Nazarbayev University Research and Innovation System [RB 2014-26]
- Agence Nationale de la Recherche (ANR) [ANR-10-BLAN-1617] Funding Source: Agence Nationale de la Recherche (ANR)
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 center dot 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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