Site-Specific DNA Photocleavage and Photomodulation by Oligonucleotide Conjugates

Abstract

Triplex-forming oligonucleotides have been explored in the last 3 decades as highly specific gene-modifying agents. Such agents have been showed to either upregulate or shut down gene expression in vitro, an outcome that depends on the specifically designed biological system. One interesting approach is to tether to the oligonucleotide a photoreactive moiety. After hybridization to the DNA target (typically single- or double-stranded DNA), a site-specific photoinduced reaction may take place at a timely manner. Further, as the light source may be focused at a certain area, one has control on the location at which the phototriggered DNA modification takes place. In this regard, the use of tissue-penetrating photons (typically 630-950 nm) would be most relevant for in vivo applications as photoactivation may lead to site-specific DNA modification at a specific tissue/organ. In this review we highlight the advances made in this field and discuss the hurdles that lay ahead for the realization of phototriggered triplex-forming oligonucleotides as a solid therapeutic approach.

Molecular Engineering of Guanine-Rich Sequences: Z-DNA, DNA Triplexes, and G-Quadruplexes

“…Such TFO conjugates can be used to study molecular mechanisms of DNA repair, recombination, and mutagenesis. The termini of GROs have been modified with psoralen, pyrene (Figure ), and other derivatives; we refer an interested reader to several comprehensive reviews published in this field. ,,,, Recently, a sequence-specific cleaving and photo-cross-linking induced by G-quadruplex formation in telomeric DNA was reported. The phosphonic analogue of EDTA, called EDTP (Figure ), was attached to the 5′-end of a three-repeat human telomeric sequence which might assemble into a G- triplex .…”

Triplex-forming oligonucleotides as an anti-gene technique for cancer therapy

“…The photoactivation of photoactivatable derivatives-labeled TFOs could have several advantages. First, genetic manipulation could be controlled at the target location and specific time; Second, light irradiation is a clean and safe intervention; Third, the photoinduced targeted gene damage would be highly specific with insignificant toxic side effects ( Kolevzon and Yavin, 2010 ). Photosensitizers (PS) with strong photosensitivity and low toxin may be the potential candidates to replace psoralen for conjugate with TFOs.…”

Synthesis of Oligonucleotides Containing 4,5′,8‐Trimethylpsoralen at the 2′‐OPosition and Their Cross‐Linking Properties with RNAs

“…Photoresponsive oligonucleotide analogues which cross-link with complementary oligonucleotides using photo-irradiation as a trigger of the reaction have been developed to investigate and control gene functions without damaging living systems (Thoung and Asseline, 2009;Kolevzon and Yavin, 2010). These oligonucleotide analogues have photoresponsive moieties introduced on a site that does not affect duplex or triplex formation.…”