The paradox of R-loops: guardians of the genome or drivers of disease?

R-loops, chromatin structures containing DNA–RNA hybrids with displaced single-stranded DNA, play crucial roles in various cellular processes. Their formation is influenced by factors such as DNA topology, RNA stability, and the presence of GC-rich regions. However, excessive or uncontrolled R-loop accumulation can threaten genomic stability, leading to DNA damage, particularly double-strand breaks. To preserve genome integrity, cells have developed mechanisms to regulate R-loop formation and resolution. Dysregulation of these processes is linked to several diseases, including cancer and neurodegenerative disorders. In this review, we will explore the dynamics of R-loop formation and resolution and how they are detected, their roles in DNA damage and repair, and how their dysregulation may lead to immune responses and disease pathogenesis.