R-loop generation during transcription: Formation, processing and cellular outcomes

R-loops are structures consisting of an RNA-DNA duplex and an unpaired DNA strand. They can form during transcription upon nascent RNA "threadback" invasion into the DNA duplex to displace the non-template strand. Although R-loops occur naturally in all kingdoms of life and serve regulatory roles, they are often deleterious and can cause genomic instability. Of particular importance are the disastrous consequences when replication forks or transcription complexes collide with R-loops. The appropriate processing of R-loops is essential to avoid a number of human neurodegenerative and other clinical disorders. We provide a perspective on mechanistic aspects of R-loop formation and their resolution learned from studies in model systems. This should contribute to improved understanding of R-loop biological functions and enable their practical applications. We propose the novel employment of artificially-generated stable R-loops to selectively inactivate tumor cells.