Human telomeric sequence forms a hybrid-type intramolecular G-quadruplex structure with mixed parallel/antiparallel strands in potassium solution
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ID: 297727
2006
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Abstract
Human telomeric DNA consists of tandem repeats of the sequence d(TTAGGG).The formation and stabilization of DNA G-quadruplexes in the human telomeric sequence have been shown to inhibit the activity of telomerase, thus the telomeric DNA G-quadruplex has been considered as an attractive target for cancer therapeutic intervention.However, knowledge of the intact human telomeric G-quadruplex structure(s) formed under physiological conditions is a prerequisite for structure-based rational drug design.Here we report the folding structure of the human telomeric sequence in K 1 solution determined by NMR.Our results demonstrate a novel, unprecedented intramolecular G-quadruplex folding topology with hybrid-type mixed parallel/antiparallel G-strands.This telomeric G-quadruplex structure contains three G-tetrads with mixed G-arrangements, which are connected consecutively with a double-chain-reversal side loop and two lateral loops, each consisting of three nucleotides TTA.This intramolecular hybridtype telomeric G-quadruplex structure formed in K 1 solution is distinct from those reported on the 22 nt Tel22 in Na 1 solution and in crystalline state in the presence of K 1 , and appears to be the predominant conformation for the extended 26 nt telomeric sequence Tel26 in the presence of K 1 , regardless of the presence or absence of Na 1 .Furthermore, the addition of K 1 readily converts the Na 1 -form conformation to the K 1 -form hybrid-type G-quadruplex.Our results explain all the reported experimental data on the human telomeric G-quadruplexes formed in the presence of K 1 , and provide important insights for understanding the polymorphism and interconversion of various G-quadruplex structures formed within the human telomeric sequence, as well as the effects of sequence and cations.This hybrid-type G-quadruplex topology suggests a straightforward pathway for the secondary structure formation with effective packing within the extended human telomeric DNA.The hybrid-type telomeric G-quadruplex is most likely to be of pharmacological relevance, and the distinct folding topology of this G-quadruplex suggests that it can be specifically targeted by G-quadruplex interactive small molecule drugs.
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| Authors | Attila Ambrus, D. Chen, Jixun Dai, Tiffanie Bialis, Roger A. Jones, Danzhou Yang |
| Journal | Nucleic Acids Research |
| Year | 2006 |
| DOI |
10.1093/nar/gkl348
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| URL | |
| Keywords | Keywords not found |
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