Issue 92, 2022

Long-range DNA interactions: inter-molecular G-quadruplexes and their potential biological relevance

Abstract

Guanine-rich DNA sequences are known to fold into secondary structures called G-quadruplexes (G4s), which can form from either individual DNA strands (intra-molecular) or multiple DNA strands (inter-molecular, iG4s). Intra-molecular G4s have been the object of extensive biological investigation due to their enrichment in gene-promoters and telomers. On the other hand, iG4s have never been considered in biological contexts, as the interaction between distal sequences of DNA to form an iG4 in cells was always deemed as highly unlikely. In this feature article, we challenge this dogma by presenting our recent discovery of the first human protein (CSB) displaying astonishing picomolar affinity and binding selectivity for iG4s. These findings suggest potential for iG4 structures to form in cells and highlight the need of further studies to unravel the fundamental biological roles of these inter-molecular DNA structures. Furthermore, we discuss how the potential for formation of iG4s in neuronal cells, triggered by repeat expansions in the C9orf72 gene, can lead to the formation of nucleic-acids based pathological aggregates in neurodegenerative diseases like ALS and FTD. Finally, based on our recent work on short LNA-modified probes, we provide a prespective on how the rational design of G4-selective chemical tools can be leveraged to further elucidate the biological relevance of iG4 structures in the context of ageing-related diseases.

Graphical abstract: Long-range DNA interactions: inter-molecular G-quadruplexes and their potential biological relevance

Article information

Article type
Feature Article
Submitted
02 sep. 2022
Accepted
19 oct. 2022
First published
19 oct. 2022
This article is Open Access
Creative Commons BY license

Chem. Commun., 2022,58, 12753-12762

Long-range DNA interactions: inter-molecular G-quadruplexes and their potential biological relevance

D. Liano, L. Monti, S. Chowdhury, F. Raguseo and M. Di Antonio, Chem. Commun., 2022, 58, 12753 DOI: 10.1039/D2CC04872H

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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