Journal
NUCLEIC ACIDS RESEARCH
Volume 41, Issue 22, Pages 10323-10333Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkt813
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Funding
- NIH [R01ES0515052, R01GM032431, R00ES016758, R01GM031973]
- Division of Intramural Research of the National Institutes of Health, NIEHS [Z01 ES065070]
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Previous evidence indicates that telomeres resemble common fragile sites and present a challenge for DNA replication. The precise impediments to replication fork progression at telomeric TTAGGG repeats are unknown, but are proposed to include G-quadruplexes (G4) on the G-rich strand. Here we examined DNA synthesis and progression by the replicative DNA polymerase d/proliferating cell nuclear antigen/replication factor C complex on telomeric templates that mimic the leading C-rich and lagging G-rich strands. Increased polymerase stalling occurred on the G-rich template, compared with the C-rich and nontelomeric templates. Suppression of G4 formation by substituting Li+ for K+ as the cation, or by using templates with 7-deaza-G residues, did not alleviate Pol delta pause sites within the G residues. Furthermore, we provide evidence that G4 folding is less stable on single-stranded circular TTAGGG templates where ends are constrained, compared with linear oligonucleotides. Artificially stabilizing G4 structures on the circular templates with the G4 ligand BRACO-19 inhibited Pol d progression into the G-rich repeats. Similar results were obtained for yeast and human Pol d complexes. Our data indicate that G4 formation is not required for polymerase stalling on telomeric lagging strands and suggest that an
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