Fig. 2.

Causes and consequences of conflicts between Pol I transcriptional and replication machineries. The indicated oncogenic signaling pathways can lead an aberrant increase in the rate of Pol I transcription. Convergence of Pol I and replication machineries in head-on orientation leads to the accumulation of positive DNA supercoiling, which slows down both machineries. Negative DNA supercoiling forming behind transcription bubble leads to opening of rDNA strands and the formation of highly stable rRNA:rDNA hybrids, leaving the displaced non-template strand. The rDNA genes are predilection sites for the formation of R- loops owing to the presence of a region of GC skewing, downstream of unmethylated CpG island rDNA promoters. Clashes of Pol I transcriptional machinery and R-loops with replication fork may cause its stalling or collapse. Perturbing replication of rDNA may further potentiate conflicts between replicating forks and Pol I transcriptional machinery as well as generation and stabilization of co-transcriptional R-loops and R-loop dependent rDNA damage. Several protective and DNA repair mechanisms are shown that preserve genome stability upon conflicts between Pol I transcriptional and replication machineries, thus preventing tumorigenesis. Asterisks indicate DNA damage