Fig. 6: Model of the regulation of TRCs in the human genome.
From: Topoisomerase 1 prevents replication stress at R-loop-enriched transcription termination sites
a Highly expressed genes form co-transcriptional R-loops at TSS, TTS and to a lesser extent in gene bodies. Replication origins are frequently located upstream of TSS. b Initiation from upstream origins ensures that R-loops at TSS and gene bodies are preferentially replicated codirectionally, which would limit HO conflicts. Forks progressing in the opposite direction pause when they encounter the TTS of highly expressed genes, presumably because of the accumulation of positive supercoiling. Transient fork pausing activates ATR and leads to the phosphorylation of RPA32 on S33. ATR may also promote the displacement of RNA polymerases ahead of the paused fork. c In the absence of Top1, the accumulation of torsional stress may lead to fork collapse and to the sustained activation of ATR/ATM. This would in turn slowdown fork progression throughout the genome.
