Abstract
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.
Highlights
Functional Organization of the Genome Group, Centro de Biología Molecular “Severo Ochoa”, Consejo Superior de Investigaciones Científicas/Universidad Autónoma de Madrid, Madrid, Spain
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
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
Summary
Received: 21 February 2015 Paper pending published: 16 March 2015 Accepted: 08 April 2015 Published: 28 April 2015. The earliest evidence for a role for R-loops in initiation of DNA replication came from studies in the late 1980’s on Escherichia coli plasmid ColEI In this system, a transcript initiated from an upstream promoter forms a persistent hybrid with the template strand within specific origin elements (Dasgupta et al, 1987; Masukata and Tomizawa, 1990). The RNA of the R-loop can serve as an effective primer for elongation by POLG, the mtDNA polymerase These findings are reminiscent of those described for ColEI replication (Masukata et al, 1987), indicating that stable R-loop formation depends on C-rich clusters on template DNA. That R-loop formation during cSDR occurs by transcript invasion, in contrast to the co-transcriptional R-loops generated in ColE1 replication (Kogoma, 1997)
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