Figure 4.

Pathways used to resolve a transcription–replication conflict. (A) When faced with a transcriptional block, the replisome (in blue) can skip the RNAP (in orange) and reprime downstream using the PRIM1 primase when the block is on the lagging strand, or the PRIMPOL1 polymerase when the block is on the leading strand. (B) In case of a CD conflict, the replisome can also displace the RNAP and use the hybridized RNA as a primer to reinitiate replication. (C) Numerous pathways exist to simply remove and, in some cases, degrade the RNAP and the potential associated R-loops from the chromatin to allow continuous DNA synthesis. (D) In case of persistent RNAP complexes, the replication fork can undergo fork reversal to stabilize the fork and give time to resolve the conflict by the above-mentioned mechanisms. (E) The reversed fork can also undergo a cycle of fork cleavage and re-ligation. This mechanism uses RECQ5 to inhibit fork reversal and the endonuclease MUS81 to cleave the fork. This relieves torsional stress, and the fork can then be re-ligated by RAD52 and LIG4 that in turn allows the resumption of transcription and the removal of the replisome block.