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Mechanism of acridine-based telomerase inhibition and telomere shortening

2007; Elsevier BV; Volume: 74; Issue: 5 Linguagem: Inglês

10.1016/j.bcp.2007.06.011

1873-2968

Mekala Gunaratnam, Olga Greciano, Cristina Martins, Anthony P. Reszka, Christoph Schultes, Hamid Morjani, Jean‐François Riou, Stephen Neidle,

RNA Interference and Gene Delivery

The trisubstituted acridine compound BRACO-19 has been developed as a ligand for stabilising G-quadruplex structures. It is shown here that BRACO-19 produces short- and long-term growth arrest in cancer cell lines, and is significantly less potent in a normal cell line. BRACO-19 reduces telomerase activity and long-term telomere length attrition is observed. It is also shown that BRACO-19 binds to telomeric single-stranded overhang DNA, consistent with quadruplex formation, and the single-stranded protein hPOT1 has been shown to be displaced from the overhang in vitro and in cellular experiments. It is concluded that the cellular activity of BRACO-19 can be ascribed both to the uncapping of 3′ telomere ends and to telomere shortening that may preferentially affect cells with short telomeres.