CoII(Chromomycin)2 Complex Induces a Conformational Change of CCG Repeats from i-Motif to Base-Extruded DNA Duplex

Abstract

We have reported the propensity of a DNA sequence containing CCG repeats to form a stable i-motif tetraplex structure in the absence of ligands. Here we show that an i-motif DNA sequence may transition to a base-extruded duplex structure with a GGCC tetranucleotide tract when bound to the (CoII)-mediated dimer of chromomycin A3, CoII(Chro)2. Biophysical experiments reveal that CCG trinucleotide repeats provide favorable binding sites for CoII(Chro)2. In addition, water hydration and divalent metal ion (CoII) interactions also play a crucial role in the stabilization of CCG trinucleotide repeats (TNRs). Our data furnish useful structural information for the design of novel therapeutic strategies to treat neurological diseases caused by repeat expansions.

Gene expression profiles complement the analysis of genomic modifiers of the clinical onset of Huntington disease

“…Employing this approach, informed by genetic data generated from numerous HD patients, yielded a number of leads for future research. These include chromomycin, which has been proposed as a potential therapeutic target for neurological disorders caused by repeat expansions ( 42 ), as well as mitoxantrone and guanabenz, which have been implicated as potential medications for multiple sclerosis ( 43 , 44 ). Additionally, anthracyclines have been shown to correct gene expression perturbations in HD mice ( 45 ), whereas BMS-345541 ( 46 ) and the histone deacetylase inhibitor, trichostatin-a ( 47 ), have been shown to restore HD-related deficits in vitro .…”

Gene expression profiles complement the analysis of genomic modifiers of the clinical onset of Huntington disease

“…46 Employing this approach, informed by genetic data generated from numerous HD patients, yielded a number of leads for future research. These include: chromomycin, which has been proposed as a potential therapeutic target for neurological disorders caused by repeat expansions; 47 as well as mitoxantrone and guanabenz, which have been implicated as potential medications for multiple sclerosis. 48, 49 Additionally, anthracyclines have been shown to correct gene expression perturbations in HD mice, 50 while BMS-345541 51 and the histone deacetylase inhibitor, trichostatin-a, 52 have been shown to restore HD-related deficits in vitro.…”

The i-Motif as a Molecular Target: More Than a Complementary DNA Secondary Structure

“…Depending on the location, the extra stretches of repeats disrupt the reading frame for proper gene expression and increase the likelihood for secondary structure formation, which can further perturb gene replication and transcription. Nucleotide repeat expansions with repeated G/C sequences are implicated in several human diseases including fragile X syndrome (CGG), progressive myoclonus epilepsy (CCCCGCCCCGCG), and amyotrophic lateral sclerosis/frontotemporal dementia (GGGGCC) [147][148][149].…”

“…FRM1 is susceptible to expanded C-repeats, which are known to form i-motif structures and thought to play a role in suppressing expression of this gene [29]. A recent study revealed that the addition of a metal complex CoII(Chromomycin) 2 causes the i-motif structures to transition into duplex DNA [147]. CoII(Chromomycin) 2 complex preferentially binds to the duplex conformation of DNA and the authors suggest that this metal complex may prevent i-motif formation by forcing the DNA to remain in double-stranded form and, in turn, minimize polymerase slippage and inhibit further repeat expansion [147].…”