The Tale of the Guanosine Tract in Repeat Expansion Disorders

Repeat expansion disorders (REDs) constitute a major class of neurological and neuromuscular pathologies that affect millions worldwide. Guanosine (G)-rich sequences are often implicated in these disorders due to their ability to adopt highly stable, non-canonical secondary structures that trigger genomic instability. These include but are not limited to conformations such as G-quadruplexes (G4s), hairpins and R-loops that can critically alter the cell's molecular events. Herein, we focused on how guanosine governs the formation of diverse secondary structures and discussed the array of G-rich tracts that are known to trigger various REDs. We pinpoint the key molecular mechanisms through which these G-tracts contribute to disease onset and progression. Emphasis has been laid on the interconnected nature of these mechanisms that ultimately converge and reinforce one another to drive various cellular dysfunctions. Targeting these shared molecular nodes through small-molecule disruptors, R-loop resolving approaches, antisense oligonucleotides (ASOs) and clustered regularly interspaced short palindromic repeats (CRISPR)-based genome editing holds significant translational potential across a multitude of REDs. Lastly, we highlight the potential of integrative multi-omics and structural approaches to understand the equilibrium orchestrated by cellular processes that ultimately dictates whether G-tracts function as genome regulators or evolve into pathological hotspots.