Novel Anticancer Strategy Aimed at Targeting Shelterin Complexes by the Induction of Structural Changes in Telomeric DNA: Hitting Two Birds with One Stone.

Novel Anticancer Strategy Aimed at Targeting Shelterin Complexes by the Induction of Structural Changes in Telomeric DNA: Hitting Two Birds with One Stone.
Curr Cancer Drug Targets. 2014 Jan 20;
Authors: Bidzinska J, Baginski M, Skladanowski A
Abstract
The ends of chromosomes in mammals are composed of telomeric DNA containing TTAGGG repeats, which bind specific proteins called shelterins. This telomeric DNA together with shelterins form a cap that protects the ends of chromosomes from being recognized as sites of DNA damage and from chromosomal fusions. Many very successful antitumor drugs used in the treatment of cancer patients bind to DNA, some of them with a prominent sequence specificity that leads to changes in DNA structure and integrity. We propose a new target for antitumor drugs where small molecule ligands can bind to telomeric DNA and induce specific structural changes. These changes would lead to a selective interference with the formation of telomeric DNA-shelterin complexes, especially involving TRF1 and TRF2 proteins, as these proteins bind double-stranded telomeric DNA in a sequence- and structure-dependent manner. The rationale of the proposed therapeutic strategy is further justified by the fact that tumor cells have relatively short telomeres and frequently de-regulated shelterin expression and/or functionality. Thus uncapping of chromosome ends by DNA binding compounds which disrupt DNA-shelterin complexes can ultimately ...

Source: Current Cancer Drug Targets - January 20, 2014 Category: Cancer & Oncology Authors: Bidzinska J, Baginski M, Skladanowski A Tags: Curr Cancer Drug Targets Source Type: research