Novel Anticancer Strategy Aimed at Targeting Shelterin Complexes by the Induction of Structural Changes in Telomeric DNA: Hitting two Birds with one Stone
Joanna Bidzinska, Maciej Baginski and Andrzej Skladanowski
Affiliation: Laboratory of Molecular and Cellular Pharmacology, Department of Pharmaceutical Technology and Biochemistry, Gdansk University of Technology, Narutowicza St 11/12, 80-233 Gdansk, Poland.
Keywords: Anticancer agent, DNA binding, shelterin, telomere, TRF1, TRF2, telomeric DNA.
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 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 induce selective cytotoxic effect in tumor
cells. Possible implications for rational design of new antitumor drugs which interfere with telomeric DNA structure and
formation of DNA-shelterin complexes are discussed.
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