Insight into tetramolecular DNA G-quadruplexes associated with ALS and FTLD : cation interactions and formation of higher-ordered structure

Zalar, Matja (author), Wang, Baifan (author), Plavec, Janez (author), Šket, Primož (author)

The G$_4$C$_2$ hexanucleotide repeat expansion in the c9orf72 gene is a major genetic cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), with the formation of G-quadruplexes directly linked to the development of these diseases. Cations play a crucial role in the formation and structure of G-quadruplexes. In this study, we investigated the impact of biologically relevant potassium ions on G-quadruplex structures and utilized $^{15}$N-labeled ammonium cations as a substitute for K$^+$ ions to gain further insights into cation binding and exchange dynamics. Through nuclear magnetic resonance spectroscopy and molecular dynamics simulations, we demonstrate that the single d(G$_4$C$_2$) repeat, in the presence of $^{15}$NH$_4{}^+$ ions, adopts a tetramolecular G-quadruplex with an all-syn quartet at the 5′-end. The movement of $^{15}$NH$_4{}^+$ ions through the central channel of the G-quadruplex, as well as to the bulk solution, is governed by the vacant cation binding site, in addition to the all-syn quartet at the 5′-end. Furthermore, the addition of K$^+$ ions to G-quadruplexes folded in the presence of $^{15}$NH$_4{}^+$ ions induces stacking of G-quadruplexes via their 5′-end G-quartets, leading to the formation of stable higher-ordered species.

• Language: English
• Keywords: ALS, FTLD, DNA, c9orf7, NMR, quadruplex, cations
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FKKT - Faculty of Chemistry and Chemical Technology
• Publication status: Published
• Publication version: Version of Record
• Year: 2023
• Number of pages: 19 str.
• Numbering: Vol. 24, iss. 17, art. 13437
• PID: 20.500.12556/RUL-164845
• UDC: 544.1
• ISSN on article: 1422-0067
• DOI: 10.3390/ijms241713437
• COBISS.SI-ID: 162931971
• Publication date in RUL: 13.11.2024

Record is a part of a journal

• Title: International journal of molecular sciences
• Shortened title: Int. j. mol. sci.
• Publisher: MDPI
• ISSN: 1422-0067
• COBISS.SI-ID: 2779162

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: biokemija, tetramolekule, kationi, kvadrupleksi, DNK, amiotrofična lateralna skleroza