We have recently reported that topoisomerase 1 (Top1) cooperates with ASF/SF2, a 
splicing factor of the SR family, to prevent unscheduled replication fork arrest 
and genomic instability in human cells. Our results suggest that Top1 execute 
this function by suppressing the formation of DNA-RNA hybrids during 
transcription, these so-called R-loops interfering with the progression of 
replication forks. Using ChIP-chip, we have shown that γ-H2AX, a marker of DNA 
damage, accumulates at gene-rich regions of the genome in Top1-deficient cells. 
This is best illustrated at histone genes, which are highly expressed during S 
phase and display discrete γ-H2AX peaks on ChIP-chip profiles. Here, we show 
that these γ-H2AX domains are different from those induced by camptothecin, a 
Top1 inhibitor inducing double-strand DNA breaks throughout the genome. These 
data support the view that R-loops promote genomic instability at specific sites 
by blocking fork progression and inducing chromosome breaks. Whether this type 
of transcription-dependent fork arrest contributes to the replication stress 
observed in precancerous lesions is an important question that deserves further 
attention.