Aberrant repair initiated by mismatch-specific thymine-DNA glycosylases provides a mechanism for the mutational bias observed in CpG islands
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Date
2014-04-01
Authors
Talhaoui, Ibtissam
Couve, Sophie
Gros, Laurent
Ishchenko, Alexander A.
Matkarimov, Bakhyt
Saparbaev, Murat K.
Journal Title
Journal ISSN
Volume Title
Publisher
Nucleic Acids Research
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,N6-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→CpGmutations,
thus providing a plausible mechanism for the putative
evolutionary origin of the CGIs in mammalian
genomes.
Description
Keywords
aberrant repair, mismatch-specific thymine-DNA
Citation
Talhaoui, I., Couve, S., Gros, L., Ishchenko, A. A., Matkarimov, B., & Saparbaev, M. K. (2014). Aberrant repair initiated by mismatch-specific thymine-DNA glycosylases provides a mechanism for the mutational bias observed in CpG islands. Nucleic Acids Research, 42(10), 6300–6313. http://doi.org/10.1093/nar/gku246