A) Accessory helicases including Rep (E. coli), PcrA (B. subtilis), Rrm3, Sen1 (yeast) or SETX (human) can assist the replicative helicase by dislodging transcription complexes ahead of the replication fork.
B) The S-phase checkpoint can monitor and respond to replication forks stalled at transcription complexes in eukaryotic cells. The Mec1/ATR kinase may promote fork progression and stability at transcribed genes by phosphorylating the nucleoporin Mlp1, thereby releasing genes from the nuclear pore to reduce topological tension. The checkpoint also controls tRNA gene transcription mediated by the Maf1 repressor to reduce interference with replication. The osmostress-induced protein kinase Hog1 phosphorylates Mrc1, a downstream component of the Mec1/ATR pathway, thereby preventing early origin firing and fork progression to prevent TRCs during osmostress. In addition, Mec1/ATR, in cooperation with INO80 and PAF1C, can trigger the efficient removal of chromatin-bound RNAPII near early firing origins. NPC, Nuclear Pore Complex
C) Replication forks stalled at transcription complexes can resume DNA synthesis by different fork restart and DNA repair pathways. (i) A replication fork stalled at a transcription complex can be rescued by firing of an adjacent dormant origin. This back-up replication fork encounters the transcription complex from the opposite direction and may represent a second chance to remove the transcription block and resume DNA synthesis. Alternatively, replication forks stalled at TRCs may be stabilized by ATR, BRCA2, or the FA-pathway (ii). Prolonged stalling of the replication fork may also promote re-annealing of parental strands priming fork reversal. Removal of the transcription block by one or several of the pathways/factors listed can then promote fork restart (iii). If the transcription block persists, this may ultimately lead to fork breakage (iv). Break-induced replication (BIR) and/or homologous recombination (HR)-dependent repair mechanisms may then be used to overcome the obstacle.