The unanticipated widespread occurrence of stable hybrid DNA/RNA structures 
(R-loops) in human cells and the increasing evidence of their involvement in 
several human malignancies have invigorated the research on R-loop biology in 
recent years. Here we propose that physiological R-loop formation at CpG island 
promoters can contribute to DNA replication origin specification at these 
regions, the most efficient replication initiation sites in mammalian cells. 
Quite likely, this occurs by the strand-displacement reaction activating the 
formation of G-quadruplex structures that target the origin recognition complex 
(ORC) in the single-stranded conformation. In agreement with this, we found that 
R-loops co-localize with the ORC within the same CpG island region in a 
significant fraction of these efficient replication origins, precisely at the 
position displaying the highest density of G4 motifs. This scenario builds on 
the connection between transcription and replication in human cells and suggests 
that R-loop dysregulation at CpG island promoter-origins might contribute to the 
phenotype of DNA replication abnormalities and loss of genome integrity detected 
in cancer cells.