RESEARCH

This study shows that replisome progression actively regulates transcription at R-loop-forming genes, revealing an unexpected bidirectional crosstalk between DNA replication, transcription, and R-loops within a single cell cycle. Using live-cell imaging in budding yeast, the authors show that WT replisomes traverse R-loop-prone sequences robustly, while loss of resolution factors impairs fork progression. Importantly, R-loop formation suppresses local RNAPII occupancy and transcription — an inhibitory state that is rapidly and actively reversed upon replisome passage, establishing replication-coupled transcriptional re-activation as a previously unrecognized mechanism.

The study also uncovers a protective role for R-loops: by reducing RNAPII density at highly expressed genes, R-loops can prevent the very fork stalling that would otherwise arise from excessive polymerase occupancy. Together, these findings reframe R-loops as dynamic, context-dependent modulators of genome stability rather than uniformly pathological structures, with broader implications for understanding how replication stress and R-loop dysregulation contribute to cancer and neurological disease.