E-motif formed by extrahelical cytosine bases in DNA homoduplexes of trinucleotide and hexanucleotide repeats

Pan, Feng; Zhang, Y.; Man, Viet Hoang; Roland, Christopher; Sagui, Celeste

doi:10.1093/nar/gkx1186

Cited by 19 publications

(35 citation statements)

References 54 publications

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“…The extruded cytosines thus form an e-motif structure which might stabilize the packing of the complex within the crystal lattice. The presence of such structures has been reported previously [ 17 , 18 , 19 ]. Analysis of the crystal structures revealed that Co II (Chro) 2 altered the formation of the i-motif tetraplex, which was composed of two hairpin-like structures.…”

Section: Resultssupporting

confidence: 70%

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

Chen

Satange

et al. 2018

IJMS

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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.

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Section: Resultssupporting

confidence: 70%

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

Chen

Satange

et al. 2018

IJMS

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“…We showed that the e-motif is stable under the three modifications of the DNA force field, mainly BSC0, BSC1, and OL15. 44 In Figure 5, we show that free energy maps for these three force fields all share the same free energy minima (in terms of the dihedral angles χ ) for the mismatch conformations. The barriers between the different minima are lowest for BSC0 and highest for BSC1 (barriers for OL15 are intermediate).…”

Section: Resultsmentioning

confidence: 88%

“…The pattern of stabilizing hydrogen bonds for GCC4 with an extended e-motif depends on the force field: OL15 consistently displays intrastrand C i (N4)–C ( i –2) (O2) bonding, BSC0 shows a mix of intra- and interstrand bonding, and BSC1 shows interstrand bondings between the N4 atom of the C i mismatched base in one strand and the O4′ atom of the second Watson–Crick paired C in the opposite strand (i.e., C6–C27, C9–C24, etc.). 44 Hydrogen bond populations for the extruded C’s in the extended e-motif are also shown in Figure 11c. Figure 12a shows the total handedness of the middle three regular (Watson–Crick) CpG steps for the extended e-motif.…”

Section: Resultsmentioning

confidence: 98%

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Structure and Dynamics of DNA and RNA Double Helices Obtained from the CCG and GGC Trinucleotide Repeats

et al. 2018

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Expansions of both GGC and CCG sequences lead to a number of expandable, trinucleotide repeat (TR) neurodegenerative diseases. Understanding of these diseases involves, among other things, the structural characterization of the atypical DNA and RNA secondary structures. We have performed molecular dynamics simulations of (GCC) and (GGC) homoduplexes in order to characterize their conformations, stability, and dynamics. Each TR has two reading frames, which results in eight nonequivalent RNA/DNA homoduplexes, characterized by CpG or GpC steps between the Watson-Crick base pairs. Free energy maps for the eight homoduplexes indicate that the C-mismatches prefer anti-anti conformations, while G-mismatches prefer anti-syn conformations. Comparison between three modifications of the DNA AMBER force field shows good agreement for the mismatch free energy maps. The mismatches in DNA-GCC (but not CCG) are extrahelical, forming an extended e-motif. The mismatched duplexes exhibit characteristic sequence-dependent step twist, with strong variations in the G-rich sequences and the e-motif. The distribution of Na is highly localized around the mismatches, especially G-mismatches. In the e-motif, there is strong Na binding by two G(N7) atoms belonging to the pseudo GpC step created when cytosines are extruded and by extrahelical cytosines. Finally, we used a novel technique based on fast melting by means of an infrared laser pulse to classify the relative stability of the different DNA-CCG and -GGC homoduplexes.

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“…Here, it was shown that the composition and the length of the repeat determine the propensity to form secondary structures, such as hairpins. The structure and the dynamics of both DNA and RNA duplexes of CAG, GAC, CCG, and GGC trinucleotide repeats have been studied by molecular modeling revealing that A-A non-canonical pairs form high-anti conformations in DNA [ 113 ] and that mismatches in C-rich hairpin stems are weakly bonded and may flip out forming “e-motifs” [ 114 , 115 ]. Although these studies provide interesting insights, the detailed dynamics of these processes inside the nucleus of neuronal cells remains to be elucidated.…”

Section: Structural Properties and Genomic Instability Of Repeatsmentioning

confidence: 99%

Targeted Oligonucleotides for Treating Neurodegenerative Tandem Repeat Diseases

Zain

Smith

2019

Neurotherapeutics

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Nucleotide repeat disorders encompass more than 30 diseases, most of which show dominant inheritance, such as Huntington's disease, spinocerebellar ataxias, and myotonic dystrophies. Yet others, including Friedreich's ataxia, are recessively inherited. A common feature is the presence of a DNA tandem repeat in the disease-associated gene and the propensity of the repeats to expand in germ and in somatic cells, with ensuing neurological and frequently also neuromuscular defects. Repeat expansion is the most frequent event in these diseases; however, sequence contractions, deletions, and mutations have also been reported. Nucleotide repeat sequences are predisposed to adopt non-B-DNA conformations, such as hairpins, cruciform, and intramolecular triple-helix structures (triplexes), also known as H-DNA. For gain-of-function disorders, oligonucleotides can be used to target either transcripts or duplex DNA and in diseases with recessive inheritance oligonucleotides may be used to alter repressive DNA or RNA conformations. Most current treatment strategies are aimed at altering transcript levels, but therapies directed against DNA are also emerging, and novel strategies targeting DNA, instead of RNA, are described. Different mechanisms using modified oligonucleotides are discussed along with the structural aspects of repeat sequences, which can influence binding modes and efficiencies.Key Words Chromatin . DNA repair . fragile X syndrome . locked nucleic acid . spinal and bulbar muscular atrophy . non-canonical DNA structure Neurotherapeutics (2019) 16:248-262 https://doi.

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E-motif formed by extrahelical cytosine bases in DNA homoduplexes of trinucleotide and hexanucleotide repeats

Cited by 19 publications

References 54 publications

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

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

Structure and Dynamics of DNA and RNA Double Helices Obtained from the CCG and GGC Trinucleotide Repeats

Targeted Oligonucleotides for Treating Neurodegenerative Tandem Repeat Diseases

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