Conformation and stability of intramolecular telomeric G-quadruplexes: sequence effects in the loops

Telomeres are guanine-rich sequences that protect the ends of chromosomes. These regions can fold into G-quadruplex structures and their stabilization by G-quadruplex ligands has been employed as an anticancer strategy. Genetic analysis in human telomeres revealed extensive allelic variation restric...

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Bibliographic Details
Published in:PloS one 2013-12, Vol.8 (12), p.e84113-e84113
Main Authors: Sattin, Giovanna, Artese, Anna, Nadai, Matteo, Costa, Giosuè, Parrotta, Lucia, Alcaro, Stefano, Palumbo, Manlio, Richter, Sara N
Format: Article
Language:English
Subjects:
Analysis
Base Sequence
Chromosomes
Conformation
Deoxyribonucleic acid
DNA
G-Quadruplexes
Gel electrophoresis
Genetic analysis
Guanine
Humans
Molecular dynamics
Molecular Dynamics Simulation
Mutation
Oligonucleotides - chemistry
Oligonucleotides - genetics
Purines
Spectrum analysis
Stability analysis
Telomerase
Telomere - chemistry
Telomere - genetics
Telomeres
Thermal stability
Topology
Transition Temperature
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Summary:Telomeres are guanine-rich sequences that protect the ends of chromosomes. These regions can fold into G-quadruplex structures and their stabilization by G-quadruplex ligands has been employed as an anticancer strategy. Genetic analysis in human telomeres revealed extensive allelic variation restricted to loop bases, indicating that the variant telomeric sequences maintain the ability to fold into G-quadruplex. To assess the effect of mutations in loop bases on G-quadruplex folding and stability, we performed a comprehensive analysis of mutant telomeric sequences by spectroscopic techniques, molecular dynamics simulations and gel electrophoresis. We found that when the first position in the loop was mutated from T to C or A the resulting structure adopted a less stable antiparallel topology; when the second position was mutated to C or A, lower thermal stability and no evident conformational change were observed; in contrast, substitution of the third position from A to C induced a more stable and original hybrid conformation, while mutation to T did not significantly affect G-quadruplex topology and stability. Our results indicate that allelic variations generate G-quadruplex telomeric structures with variable conformation and stability. This aspect needs to be taken into account when designing new potential anticancer molecules.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0084113