G-Quadruplex binding enantiomers show chiral selective interactions with human telomere

Jiasi Wang,Jinsong Ren,Yong Chen,Chuanqi Zhao,Xiaogang Qu

doi:10.1093/nar/gkt1354

Jiasi Wang, Jinsong Ren + Show 3 more

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https://doi.org/10.1093/nar/gkt1354

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Abstract

Chiral recognition of DNA molecules is important because DNA chiral transition and its different conformations are involved in a series of important life events. Among them, polymorphic human telomere DNA has attracted great interests in recent years because of its important roles in chromosome structural integrity. In this report, we examine the short-term effect of chiral metallo-supramolecular complex enantiomers treatment on tumor cells, and find that a zinc-finger-like alpha helical chiral metallo-supramolecular complex, [Ni2L3]4+-P enantiomer (NiP), can selectively provoke the rapid telomere uncapping, trigger DNA damage responses at telomere and degradation of G-overhang and the delocalization of telomeric protein from telomeres. Further studies indicate that NiP can induce an acute cellular apoptosis and senescence in cancer cells rather than normal cells. These results are further evidenced by the upregulation of p21 and p16 proteins. Moreover, NiP can cause translocation of hTERT from nuclear to cytoplasm through Tyr 707 phosphorylation. While its enantiomer, [Ni2L3]4+-M (NiM), has no such mentioned effects, these results clearly demonstrate the compound’s chiral selectivity in cancer cells. Our work will shed light on design of chiral anticancer drugs targeting G-quadruplex DNA, and developing telomere and telomerase modulation agents.

Highlights

DNA chiral recognition has received much attention because more and more evidences have indicated that conversions of the chirality and diverse conformations of DNA are involved in a series of important life events
Chiral metallo-supramolecular complex NiP, but not NiM, induced cancer cell-specific growth suppression associated with the production of DNA damage response
We investigated the effect of NiP on the localization of TRF2 and POT1, two telomeric proteins inducing telomere dysfunction, and evoking DNA damage signaling when their levels are reduced at telomeres [13,56,57,58]

Summary

Introduction

DNA chiral recognition has received much attention because more and more evidences have indicated that conversions of the chirality and diverse conformations of DNA are involved in a series of important life events. Polymorphic human telomere DNA has attracted great interests in recent years because of its important roles in chromosome structural integrity to protect their extremities from illegitimate recombination, degradation and end-to-end fusion [1]. The human telomeres consist of long arrays of tandem TTAGGG repeats in double-stranded DNA (2–15 kb), with a G-rich single-stranded 30-overhang of 50–400 nucleotides. During the spontaneous replicative aging, telomere is considered as a three-state model for chromosome end protection and deprotection [2]. The ‘closed-state’ telomere was predicted to form a loop structure (t-loop/ D-loop) for chromosome end protection [3,4]. Telomere protection involves a complex of specific telomeric shelterin proteins (TRF1, TRF2, POT1, TIN2, TPP1 and Rap1) essential for genome stability [5]. Deprotected telomere due to the progressive reduction of telomere length and/or damage in telomere structure activates the DNA damage response pathways, and results in a rapid cellular growth arrest and apoptosis [6,7,8,9,10,11,12,13,14]

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