Extended Data Fig. 10: Overall working model.
From: KCTD10 is a sensor for co-directional transcription–replication conflicts
Upon encountering transcriptional roadblocks such as supercoiled DNA or trapped TOP2 (Extended Data Fig. 4m), the RNA polymerase complex attempts to backtrack and restart. At actively replicating regions, KCTD10 functions together with replication forks to sense the transcription roadblock by self-assembly which facilitates formation of a CUL3-RBX1-KCTD10 complex. This complex ubiquitinates TCEA2, which promotes TCEA2 removal and conversion of the RNAP complex back to a lower energy state41,45,46,76,77,78. This state is amenable to p97/VCP-mediated extraction, allowing the replisome to bypass the site. Whether additional factors work in parallel or downstream of KCTD10 to resolve roadblocks such as trapped TOP2 remains unclear. In the absence of KCTD10, the RNA polymerase retains TCEA2 and remains in an active elongation-competent complex that becomes permanently arrested. This disfavors replisome bypass and can lead to the generation of a persistent TRC. If this is unable to be resolved, this will eventually convert into a DSB11 and activate a DNA damage response mediated by ATM and CHK2.
