Molecular conformations and dynamics of nucleotide repeats associated with neurodegenerative diseases: double helices and CAG hairpin loops

Pan, Feng; Zhang, Y.; Xu, Pengning; Man, Viet Hoang; Roland, Christopher; Weninger, Keith; Sagui, Celeste

doi:10.1016/j.csbj.2021.04.037

Cited by 14 publications

(8 citation statements)

References 82 publications

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“…Expanded repeat tracts can occur in protein-coding sequences of particular genes, as well as in promoter sequences, introns, or in 5′- and 3′-UTRs ( Table S1 ). Interestingly, many expanded repeat tracts in RNAs are prone to the formation of stable structures like hairpins or G-quadruplexes [ 75 , 76 ]. These structures affect transcript functioning, e.g., through sequestration of proteins [ 72 ], whereas many processes remain to be investigated in this context, including APA.…”

Section: Repeat Expansion Diseasesmentioning

confidence: 99%

Implications of Poly(A) Tail Processing in Repeat Expansion Diseases

Joachimiak

Ciesiolka

Figura

et al. 2022

Cells

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Repeat expansion diseases are a group of more than 40 disorders that affect mainly the nervous and/or muscular system and include myotonic dystrophies, Huntington’s disease, and fragile X syndrome. The mutation-driven expanded repeat tract occurs in specific genes and is composed of tri- to dodeca-nucleotide-long units. Mutant mRNA is a pathogenic factor or important contributor to the disease and has great potential as a therapeutic target. Although repeat expansion diseases are quite well known, there are limited studies concerning polyadenylation events for implicated transcripts that could have profound effects on transcript stability, localization, and translation efficiency. In this review, we briefly present polyadenylation and alternative polyadenylation (APA) mechanisms and discuss their role in the pathogenesis of selected diseases. We also discuss several methods for poly(A) tail measurement (both transcript-specific and transcriptome-wide analyses) and APA site identification—the further development and use of which may contribute to a better understanding of the correlation between APA events and repeat expansion diseases. Finally, we point out some future perspectives on the research into repeat expansion diseases, as well as APA studies.

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Section: Repeat Expansion Diseasesmentioning

confidence: 99%

Implications of Poly(A) Tail Processing in Repeat Expansion Diseases

Joachimiak

Ciesiolka

Figura

et al. 2022

Cells

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“…This work forms part our endeavor to characterize the atypical secondary structures of nucleic acids associated with TREDs. Previously, we focused on DNA and RNA homoduplexes, hybrid duplexes, triplexes, quadruplexes, Z-DNA, and hairpins associated with the most common TRs (CAG, CGG, CCG, GAA, and TTC) and the hexanucleotide repeats (GGGGCC, GGCCCC, and GGGCCT). − In particular, we considered the DNA and RNA homoduplexes formed by CAG and GAC repeats complementary to the CNG and GNC (N=T or U) repeats in this study, and we harnessed the complementary role played by smFRET experiments and MD simulations in order to provide new insights into the role of sequence parity, TR interrupts, and favored type of loop structure on the dynamics of DNA CAG, GAC, CTG, and GTC hairpins. , The present study made use of MD simulations complemented with the adaptively biased molecular dynamics (ABMD) method to calculate the free energy landscapes associated with U·U (T·T) mismatches for RNA (DNA). We note that strictly speaking, the non-canonical U·U pairs in RNA are not mismatches since RNA is not necessarily self-complementary.…”

Section: Introductionmentioning

confidence: 99%

Structure and Dynamics of DNA and RNA Double Helices Formed by d(CTG), d(GTC), r(CUG), and r(GUC) Trinucleotide Repeats and Associated DNA–RNA Hybrids

Fakharzadeh,

Qu,

Pan

et al. 2023

J. Phys. Chem. B

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Myotonic dystrophy type 1 is the most frequent form of muscular dystrophy in adults caused by an abnormal expansion of the CTG trinucleotide. Both the expanded DNA and the expanded CUG RNA transcript can fold into hairpins. Cotranscriptional formation of stable RNA•DNA hybrids can also enhance the instability of repeat tracts. We performed molecular dynamics simulations of homoduplexes associated with the disease, d(CTG) n and r(CUG) n , and their corresponding r(CAG) n :d-(CTG) n and r(CUG) n :d(CAG) n hybrids that can form under bidirectional transcription and of non-pathological d(GTC) n and d(GUC) n homoduplexes. We characterized their conformations, stability, and dynamics and found that the U•U and T•T mismatches are dynamic, favoring anti−anti conformations inside the helical core, followed by anti−syn and syn−syn conformations. For DNA, the secondary minima in the non-expanding d(GTC) n helices are deeper, wider, and longer-lived than those in d(CTG) n , which constitutes another biophysical factor further differentiating the expanding and non-expanding sequences. The hybrid helices are closer to A-RNA, with the A-T and A-U pairs forming two stable Watson−Crick hydrogen bonds. The neutralizing ion distribution around the non-canonical pairs is also described.

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“…MD simulations have proven themselves to be extremely valuable as they possess the ability to probe molecular structures, dynamics, and mechanisms at the atomic level, which are often beyond the resolution of current experiment. Our recent characterization of homoduplexes, quadruplexes and hairpins conformations corresponding to the most common TRs and to several hexanucleotide repeats is an example of this, ,− as these simulations sample both DNA and RNA sequences of different lengths, different nonequivalent nucleotide arrangements (such as (GCC) n and (CCG) n homoduplexes, with CpG and GpC steps between the C–C mismatches); provide free energies, dynamics of conformational transitions, etc. These conformation studies do not address the formation of the given atypical structures: In order for these atypical structures to nucleate, it is necessary to cross a free energy barrier that is both sequence and repeat-length dependent.…”

Section: Introductionmentioning

confidence: 99%

RNA as a Major-Groove Ligand: RNA–RNA and RNA–DNA Triplexes Formed by GAA and UUC or TTC Sequences

et al. 2022

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Friedreich’s ataxia is associated with noncanonical nucleic acid structures that emerge when GAA:TTC repeats in the first intron of the FXN gene expand beyond a critical number of repeats. Specifically, the noncanonical repeats are associated with both triplexes and R-loops. Here, we present an in silico investigation of all possible triplexes that form by attaching a third RNA strand to an RNA:RNA or DNA:DNA duplex, complementing previous DNA-based triplex studies. For both new triplexes results are similar. For a pyridimine UUC+ third strand, the parallel orientation is stable while its antiparallel counterpart is unstable. For a neutral GAA third strand, the parallel conformation is stable. A protonated GA+A third strand is stable in both parallel and antiparallel orientations. We have also investigated Na+ and Mg2+ ion distributions around the triplexes. The presence of Mg2+ ions helps stabilize neutral, antiparallel GAA triplexes. These results (along with previous DNA-based studies) allow for the emergence of a complete picture of the stability and structural characteristics of triplexes based on the GAA and TTC/UUC sequences, thereby contributing to the field of trinucleotide repeats and the associated unusual structures that trigger expansion.

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Molecular conformations and dynamics of nucleotide repeats associated with neurodegenerative diseases: double helices and CAG hairpin loops

Abstract: Graphical abstract

Cited by 14 publications

References 82 publications

Implications of Poly(A) Tail Processing in Repeat Expansion Diseases

Implications of Poly(A) Tail Processing in Repeat Expansion Diseases

Structure and Dynamics of DNA and RNA Double Helices Formed by d(CTG), d(GTC), r(CUG), and r(GUC) Trinucleotide Repeats and Associated DNA–RNA Hybrids

RNA as a Major-Groove Ligand: RNA–RNA and RNA–DNA Triplexes Formed by GAA and UUC or TTC Sequences

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