Journal
DNA REPAIR
Volume 9, Issue 11, Pages 1119-1129Publisher
ELSEVIER
DOI: 10.1016/j.dnarep.2010.07.014
Keywords
Telomere; G-quadruplex; Genomic instability; DNA replication; Mutagenesis
Categories
Funding
- NIH [RO1 ES0515052, RO1 CA100060]
- Ellison Medical Foundation
- Jake Gittlen Cancer Research Foundation
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Telomeres consisting of tandem guanine-rich repeats can form secondary DNA structures called G-quadruplexes that represent potential targets for DNA repair enzymes. While G-quadruplexes interfere with DNA synthesis in vitro, the impact of G-quadruplex formation on telomeric repeat replication in human cells is not clear. We investigated the mutagenicity of telomeric repeats as a function of G-quadruplex folding opportunity and thermal stability using a shuttle vector mutagenesis assay. Since single-stranded DNA during lagging strand replication increases the opportunity for G-quadruplex folding, we tested vectors with G-rich sequences on the lagging versus the leading strand. Contrary to our prediction, vectors containing human [TTAGGG](10) repeats with a G-rich lagging strand were significantly less mutagenic than vectors with a G-rich leading strand, after replication in normal human cells. We show by UV melting experiments that G-quadruplexes from ciliates [TTGGGG](4) and [TTTTGGGG](4) are thermally more stable compared to human [TTAGGG](4). Consistent with this, replication of vectors with ciliate [TTGGGG](10) repeats yielded a 3-fold higher mutant rate compared to the human [TTAGGG](10) vectors. Furthermore, we observed significantly more mutagenic events in the ciliate repeats compared to the human repeats. Our data demonstrate that increased G-quadruplex opportunity (repeat orientation) in human telomeric repeats decreased mutagenicity, while increased thermal stability of telomeric G-quadruplexes was associated with increased mutagenicity. (C) 2010 Elsevier B.V. All rights reserved.
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