Affordable Access

deepdyve-link
Publisher Website

G-quadruplex DNA as a molecular target for induced synthetic lethality in cancer cells.

Authors
  • McLuckie, Keith I E
  • Di Antonio, Marco
  • Zecchini, Heather
  • Xian, Jian
  • Caldas, Carlos
  • Krippendorff, Ben-Fillippo
  • Tannahill, David
  • Lowe, Christopher
  • Balasubramanian, Shankar
Type
Published Article
Journal
Journal of the American Chemical Society
Publisher
American Chemical Society
Publication Date
Jul 03, 2013
Volume
135
Issue
26
Pages
9640–9643
Identifiers
DOI: 10.1021/ja404868t
PMID: 23782415
Source
Medline
License
Unknown

Abstract

Synthetic lethality is a genetic concept in which cell death is induced by the combination of mutations in two sensitive genes, while mutation of either gene alone is not sufficient to affect cell survival. Synthetic lethality can also be achieved "chemically" by combination of drug-like molecules targeting distinct but cooperative pathways. Previously, we reported that the small molecule pyridostatin (PDS) stabilizes G-quadruplexes (G4s) in cells and elicits a DNA damage response by causing the formation of DNA double strand breaks (DSB). Cell death mediated by ligand-induced G4 stabilization can be potentiated in cells deficient in DNA damage repair genes. Here, we demonstrate that PDS acts synergistically both with NU7441, an inhibitor of the DNA-PK kinase crucial for nonhomologous end joining repair of DNA DSBs, and BRCA2-deficient cells that are genetically impaired in homologous recombination-mediated DSB repair. G4 targeting ligands have potential as cancer therapeutic agents, acting synergistically with inhibition or mutation of the DNA damage repair machinery.

Report this publication

Statistics

Seen <100 times