Human telomeric sequence forms a hybrid-type intramolecular G-quadruplex structure with mixed parallel/antiparallel strands in potassium solution
By A. Ambrus, Ding Chen, J. Dai, Tiffanie Bialis, Roger A. Jones, Danzhou Yang. Nucleic Acids Research, 2006
1,036 citations recorded by the source corpus.
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+ 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 hybrid-type telomeric G-quadruplex structure formed in K+ solution is distinct from those reported on the 22 nt Tel22 in Na+ solution and in crystalline state in the presence of K+, and appears to be the predominant conformation for the extended 26 nt telomeric sequence Tel26 in the presence of K+, regardless of the presence or absence of Na+. Furthermore, the addition of K+ readily converts the Na+-form conformation to the K+-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+, 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.
Subfields: Molecular Biology
View Paper: https://www.semanticscholar.org/paper/a1991c7b3238ca0d576acf7ef920d67e63f69a16
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Citations in the corpus
- Quadruplex DNA: sequence, topology and structure (2006, methodology): “An NMR study of the bcl-2 quadruplex (94) shows that one of the topologies for this mixed parallel/anti-parallel unimolecular quadruplex has two lateral loops and one propeller loop, analogous to one of the 22mer vertebrate telomeric quadruplex topologies (75,96), but with a reversed order of loops.”
- Human telomere, oncogenic promoter and 5′-UTR G-quadruplexes: diverse higher order DNA and RNA targets for cancer therapeutics (2007, methodology): “The NMR investigation by the former group focused on the sequence d[AAAG3(T2AG3)3AA], with the resulting (3+1) topology (102) stabilized by a stacked A–A–A triple (103), associated with introduction of terminal adenine modifications (underlined) at either end of the sequence.”
- Circular dichroism and conformational polymorphism of DNA (2009, result): “This concept, which may contribute to the explanation of the gradual shortening of telomeric DNA, has generally been accepted (86,89,96) though it has not yet been confirmed by another method.”