‘From R-lupus to cancer’: reviewing the role of R-loops in innate immune responses

Cells possess an inherent and evolutionarily conserved ability to detect and respond to the presence of foreign and pathological ‘self’ nucleic acids. The result is the stimulation of innate immune responses, signalling to the host immune system that defence mechanisms are necessary to protect the organism. To date, there is a vast body of literature describing innate immune responses to various nucleic acid species, including dsDNA, ssDNA and ssRNA etc., however, there is limited information available on responses to R-loops. R-loops are 3-stranded nucleic acid structures that form during transcription, upon DNA damage and in various other settings. Emerging evidence suggests that innate immune responses may also exist for the detection of R-loop related nucleic acid structures, implicating R-loops as drivers of inflammatory states. In this review, we aim to summarise the evidence indicating that R-loops are immunogenic species that can trigger innate immune responses in physiological and pathological settings and discuss the implications of this in the study of various diseases and therapeutic development.