Repository logo

Infoscience

  • English
  • French
Log In
Logo EPFL, École polytechnique fédérale de Lausanne

Infoscience

  • English
  • French
Log In
  1. Home
  2. Academic and Research Output
  3. Journal articles
  4. Specific binding of telomeric G-quadruplexes by hydrosoluble perylene derivatives inhibits repeat addition processivity of human telomerase
 
research article

Specific binding of telomeric G-quadruplexes by hydrosoluble perylene derivatives inhibits repeat addition processivity of human telomerase

D'Ambrosio, Danilo
•
Reichenbach, Patrick
•
Micheli, Emanuela
Show more
2012
Biochimie

Telomerase is responsible for the immortal phenotype of cancer cells and telomerase inhibition may specifically target cancer cell proliferation. Ligands able to selectively bind to G-quadruplex telomeric DNA have been considered as telomerase inhibitors but their mechanisms of action have often been deduced from a non-quantitative telomerase activity assay (TRAP assay) that involves a PCR step and that does not provide insight on the mechanism of inhibition. Furthermore, quadruplex ligands have also been shown to exert their effects by affecting association of telomere binding proteins with telomeres. Here, we use quantitative direct telomerase activity assays to evaluate the strength and mechanism of action of hydrosoluble perylene diimides (HPDIs). HPDIs contain a perylene moiety and different numbers of positively charged side chains. Side chain features vary with regard to number and distances of the charges. IC50 values of HPDIs were in the low micromolar (0.5-5 mu M) range depending on the number and features of the side chains. HPDIs having four side chains emerged as the best compounds of this series. Analysis of primer elongation products demonstrated that at low HPDI concentrations, telomerase inhibition involved formation of telomeric G-quadruplex structures, which inhibited further elongation by telomerase. At high HPDI concentrations, telomerase inhibition occurred independently of G-quadruplex formation of the substrate. The mechanism of action of HPDIs and their specific binding to G-quadruplex DNA was supported by PAGE analysis, CD spectroscopy and ESI-MS. Finally, competition Telospot experiments with duplex DNA indicated specific binding of HPDIs to the single-stranded telomeric substrates over double stranded DNA, a result supported by competitive ESI-MS. Altogether, our results indicate that HPDIs act by stabilizing G-quadruplex structures in single-stranded telomeric DNA, which in turn prevents repeat addition processivity of telomerase. (C) 2011 Elsevier Masson SAS. All rights reserved.

  • Details
  • Metrics
Type
research article
DOI
10.1016/j.biochi.2011.12.004
Web of Science ID

WOS:000301332200032

Author(s)
D'Ambrosio, Danilo
Reichenbach, Patrick
Micheli, Emanuela
Alvino, Antonello
Franceschin, Marco
Savino, Maria
Lingner, Joachim  
Date Issued

2012

Published in
Biochimie
Volume

94

Start page

854

End page

863

Subjects

G-quadruplex

•

Perylene diimide

•

Telomerase

•

Telomere

•

Inhibitor

•

Telospot

•

Different Side-Chains

•

Dna Structures

•

Reverse-Transcriptase

•

Coronene Derivatives

•

Mass-Spectrometry

•

Ligands

•

Cancer

•

Cells

•

Polymorphism

•

Compound

Editorial or Peer reviewed

REVIEWED

Written at

EPFL

EPFL units
UPLIN  
Available on Infoscience
April 12, 2012
Use this identifier to reference this record
https://infoscience.epfl.ch/handle/20.500.14299/79338
Logo EPFL, École polytechnique fédérale de Lausanne
  • Contact
  • infoscience@epfl.ch

  • Follow us on Facebook
  • Follow us on Instagram
  • Follow us on LinkedIn
  • Follow us on X
  • Follow us on Youtube
AccessibilityLegal noticePrivacy policyCookie settingsEnd User AgreementGet helpFeedback

Infoscience is a service managed and provided by the Library and IT Services of EPFL. © EPFL, tous droits réservés