Abstract
Several G-rich oligodeoxynucleotides (ODNs), which are capable of forming G-quadruplexes, have been shown to exhibit antiproliferative activity against tumor cell lines and antitumor activity in nude mice carrying prostate and breast tumor xenografts. However, the molecular basis for their antitumor activity remains unclear. In the current study, we showed that a variety of telomeric G-tail oligodeoxynucleotides (TG-ODNs) exhibited antiproliferative activity against many tumor cells in culture. Systematic mutational analysis of the TG-ODNs suggests that the antiproliferative activity depends on the G-quadruplex conformation of these TG-ODNs. TG-ODNs were also shown to induce poly(ADP-ribose) polymerase-1 cleavage, phosphatidylserine flipping, and caspase activation, indicative of induction of apoptosis. TG-ODN-induced apoptosis was largely ataxia telangiectasia mutated (ATM) dependent. Furthermore, TG-ODN-induced apoptosis was inhibited by the c-Jun NH(2)-terminal kinase (JNK) inhibitor SP600125. Indeed, TG-ODNs were shown to activate the JNK pathway in an ATM-dependent manner as evidenced by elevated phosphorylation of JNK and c-Jun. Interestingly, a number of G-quadruplex ODNs (GQ-ODN) derived from nontelomeric sequences also induced ATM/JNK-dependent apoptosis, suggesting a possible common mechanism of tumor cell killing by GQ-ODNs.
Highlights
G-quadruplexes are four-stranded DNA with stacks of Gquartets formed by four guanines in a planar structure through Hoogsteen base pairing [1]
We showed that TG-ODNs in their G-quadruplex conformation were highly effective at induction of apoptosis in tumor cells
G-quadruplex ODNs (GQ-ODN) (TG24 and TG24M5)–induced phosphatidylserine flipping, monitored by Annexin V staining, was much reduced in pEBS7 (ATMÀ) compared with that in YZ5 (ATM+) cells (Fig. 4D, right). These results suggest that GQ-ODN–induced apoptosis is largely ataxia telangiectasia mutated (ATM) dependent
Summary
G-quadruplexes are four-stranded DNA with stacks of Gquartets formed by four guanines in a planar structure through Hoogsteen base pairing [1]. G-quadruplexes can be parallel or antiparallel, as well as intramolecular or intermolecular [2,3,4]. Nucleic acid sequences with multiple stretches of guanine (G) have a tendency to form thermodynamically stable G-quadruplexes. The stability is derived from hydrogen bonding within each quartet, stacking of the hydrophobic quartets on one another, and coordinating of a monovalent cation in the central channel Both nuclear magnetic resonance and X-ray crystallographic structures of G-quadruplexes have been obtained at high resolution [2, 3]. Despite the extensive study on Gquadruplex structure, its function in cells is not well understood
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