Collisions between Replication and Transcription Complexes Cause Common Fragile Site Instability at the Longest Human Genes

SummaryWe show that the time required to transcribe human genes larger than 800 kb spans more than one complete cell cycle, while their transcription speed equals that of smaller genes. Independently of their expression status, we find the long genes to replicate late. Regions of concomitant transcription and replication in late S phase exhibit DNA break hot spots known as common fragile sites (CFSs). This CFS instability depends on the expression of the underlying long genes. We show that RNA:DNA hybrids (R-loops) form at sites of transcription/replication collisions and that RNase H1 functions to suppress CFS instability. In summary, our results show that, on the longest human genes, collisions of the transcription machinery with a replication fork are inevitable, creating R-loops and consequent CFS formation. Functional replication machinery needs to be involved in the resolution of conflicts between transcription and replication machineries to ensure genomic stability.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (118 K)Download as PowerPoint slideHighlights► The time required for complete transcription of long human genes exceeds ten hours ► Collisions between transcription and replication machineries cause CFS breakage ► R-loops at the collision sites provoke the CFS instability ► Perturbed replication results in increased collision provoked fragility