Non-Canonical DNA Structures: Roles in Genome Stability and Therapeutic Potential

Repetitive DNA sequences, constituting over 50% of the human genome, were once considered evolutionary byproducts but are now recognized for their critical roles in regulating chromatin structure, gene expression, DNA replication, and genomic stability. Many of these sequences can adopt non-canonical DNA structures, such as G-quadruplexes, hairpins, and R-loops, distinct from the canonical B-DNA double helix. These structures influence key biological processes and are implicated in genome instability, making them potential therapeutic targets. Advances in genomic sequencing, structural biology, and bioinformatics have deepened our understanding of non-canonical DNA structures, DNA repair pathways, and their roles in diseases like cancer and neurodegeneration. This review explores the biological significance of non-canonical DNA, recent progress in DNA repair mechanisms, and their therapeutic potential, while highlighting challenges in targeting these structures in vivo.