Secondary structural choice of DNA and RNA associated with CGG/CCG trinucleotide repeat expansion rationalizes the RNA misprocessing in FXTAS

Abstract CGG tandem repeat expansion in the 5′-untranslated region of the fragile X mental retardation-1 (FMR1) gene leads to unusual nucleic acid conformations, hence causing genetic instabilities. We show that the number of G…G (in CGG repeat) or C…C (in CCG repeat) mismatches (other than A…T, T…A...

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Autores principales:	Yogeeshwar Ajjugal, Narendar Kolimi, Thenmalarchelvi Rathinavelan
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4430abd28b334c5da0cd323c5e8e23e2
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spelling	oai:doaj.org-article:4430abd28b334c5da0cd323c5e8e23e22021-12-02T14:26:20ZSecondary structural choice of DNA and RNA associated with CGG/CCG trinucleotide repeat expansion rationalizes the RNA misprocessing in FXTAS10.1038/s41598-021-87097-y2045-2322https://doaj.org/article/4430abd28b334c5da0cd323c5e8e23e22021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-87097-yhttps://doaj.org/toc/2045-2322Abstract CGG tandem repeat expansion in the 5′-untranslated region of the fragile X mental retardation-1 (FMR1) gene leads to unusual nucleic acid conformations, hence causing genetic instabilities. We show that the number of G…G (in CGG repeat) or C…C (in CCG repeat) mismatches (other than A…T, T…A, C…G and G…C canonical base pairs) dictates the secondary structural choice of the sense and antisense strands of the FMR1 gene and their corresponding transcripts in fragile X-associated tremor/ataxia syndrome (FXTAS). The circular dichroism (CD) spectra and electrophoretic mobility shift assay (EMSA) reveal that CGG DNA (sense strand of the FMR1 gene) and its transcript favor a quadruplex structure. CD, EMSA and molecular dynamics (MD) simulations also show that more than four C…C mismatches cannot be accommodated in the RNA duplex consisting of the CCG repeat (antisense transcript); instead, it favors an i-motif conformational intermediate. Such a preference for unusual secondary structures provides a convincing justification for the RNA foci formation due to the sequestration of RNA-binding proteins to the bidirectional transcripts and the repeat-associated non-AUG translation that are observed in FXTAS. The results presented here also suggest that small molecule modulators that can destabilize FMR1 CGG DNA and RNA quadruplex structures could be promising candidates for treating FXTAS.Yogeeshwar AjjugalNarendar KolimiThenmalarchelvi RathinavelanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yogeeshwar Ajjugal Narendar Kolimi Thenmalarchelvi Rathinavelan Secondary structural choice of DNA and RNA associated with CGG/CCG trinucleotide repeat expansion rationalizes the RNA misprocessing in FXTAS
description	Abstract CGG tandem repeat expansion in the 5′-untranslated region of the fragile X mental retardation-1 (FMR1) gene leads to unusual nucleic acid conformations, hence causing genetic instabilities. We show that the number of G…G (in CGG repeat) or C…C (in CCG repeat) mismatches (other than A…T, T…A, C…G and G…C canonical base pairs) dictates the secondary structural choice of the sense and antisense strands of the FMR1 gene and their corresponding transcripts in fragile X-associated tremor/ataxia syndrome (FXTAS). The circular dichroism (CD) spectra and electrophoretic mobility shift assay (EMSA) reveal that CGG DNA (sense strand of the FMR1 gene) and its transcript favor a quadruplex structure. CD, EMSA and molecular dynamics (MD) simulations also show that more than four C…C mismatches cannot be accommodated in the RNA duplex consisting of the CCG repeat (antisense transcript); instead, it favors an i-motif conformational intermediate. Such a preference for unusual secondary structures provides a convincing justification for the RNA foci formation due to the sequestration of RNA-binding proteins to the bidirectional transcripts and the repeat-associated non-AUG translation that are observed in FXTAS. The results presented here also suggest that small molecule modulators that can destabilize FMR1 CGG DNA and RNA quadruplex structures could be promising candidates for treating FXTAS.
format	article
author	Yogeeshwar Ajjugal Narendar Kolimi Thenmalarchelvi Rathinavelan
author_facet	Yogeeshwar Ajjugal Narendar Kolimi Thenmalarchelvi Rathinavelan
author_sort	Yogeeshwar Ajjugal
title	Secondary structural choice of DNA and RNA associated with CGG/CCG trinucleotide repeat expansion rationalizes the RNA misprocessing in FXTAS
title_short	Secondary structural choice of DNA and RNA associated with CGG/CCG trinucleotide repeat expansion rationalizes the RNA misprocessing in FXTAS
title_full	Secondary structural choice of DNA and RNA associated with CGG/CCG trinucleotide repeat expansion rationalizes the RNA misprocessing in FXTAS
title_fullStr	Secondary structural choice of DNA and RNA associated with CGG/CCG trinucleotide repeat expansion rationalizes the RNA misprocessing in FXTAS
title_full_unstemmed	Secondary structural choice of DNA and RNA associated with CGG/CCG trinucleotide repeat expansion rationalizes the RNA misprocessing in FXTAS
title_sort	secondary structural choice of dna and rna associated with cgg/ccg trinucleotide repeat expansion rationalizes the rna misprocessing in fxtas
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/4430abd28b334c5da0cd323c5e8e23e2
work_keys_str_mv	AT yogeeshwarajjugal secondarystructuralchoiceofdnaandrnaassociatedwithcggccgtrinucleotiderepeatexpansionrationalizesthernamisprocessinginfxtas AT narendarkolimi secondarystructuralchoiceofdnaandrnaassociatedwithcggccgtrinucleotiderepeatexpansionrationalizesthernamisprocessinginfxtas AT thenmalarchelvirathinavelan secondarystructuralchoiceofdnaandrnaassociatedwithcggccgtrinucleotiderepeatexpansionrationalizesthernamisprocessinginfxtas
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Secondary structural choice of DNA and RNA associated with CGG/CCG trinucleotide repeat expansion rationalizes the RNA misprocessing in FXTAS

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