We 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.