KCTD10 is a bivalent substrate sensor for the response to co-directional transcription-replication conflicts

ABSTRACT: During DNA replication, the replisome must remove barriers and roadblocks including the transcription machinery. Transcription-replication conflicts (TRCs) occur when there are collisions between the replisome and transcription machinery, and are increasingly recognized as an important source of mammalian genome instability. How cells facilitate replisome bypass at sites of TRCs is incompletely understood. Here, we show that the CUL3-KCTD10 E3 ligase senses TRCs and promotes remodeling of the RNA polymerase complex to allow replisome bypass. We found that the substrate adaptor KCTD10 interacts with both the replisome and transcription machinery and reciprocally regulates both in unstressed conditions. These bivalent interactions allow KCTD10 to detect co-directional TRCs and facilitate higher-order assembly of KCTD10 complexes that can recruit CUL3 to ubiquitinate the RNA polymerase factor TCEA2. In the absence of KCTD10 there is increased retention of TCEA2 and RNA polymerase complex, causing an accumulation of TRCs conflicts and increased DNA damage. We conclude that CUL3-KCTD10 is a sensor for co-directional TRCs that promotes remodeling of the RNA polymerase complex to permit the replisome to move through without causing DNA damage.

ORGANISM(S): Homo sapiens

PROVIDER: GSE295262 | GEO | 2025/07/31

REPOSITORIES: GEO