Novel anticancer strategy aimed at targeting shelterin complexes by the induction of structural changes in telomeric DNA: hitting two birds with one stone.
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.
Joanna
J
Bidzinska
Maciej
M
Baginski
Laboratory of Molecular and Cellular Pharmacology, Department of Pharmaceutical Technology and Biochemistry, Gdansk University of Technology, Narutowicza St 11/12, 80-233 Gdansk, Poland. as@chem.pg.gda.pl.
Andrzej
A
Skladanowski
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use*; D001665:Binding Sites; D004247:DNA / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009690:Nucleic Acid Conformation; D000089804:Shelterin Complex; D013329:Structure-Activity Relationship; D016615:Telomere / Q000187:drug effects* / Q000378:metabolism; D034501:Telomere-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D035341:Telomeric Repeat Binding Protein 2 / Q000378:metabolism
D000970:Antineoplastic Agents; D000089804:Shelterin Complex; C059329:TERF1 protein, human; C504753:TERF2 protein, human; D034501:Telomere-Binding Proteins; D035341:Telomeric Repeat Binding Protein 2; D004247:DNA