TTF2 processes sites of incomplete DNA replication during mitosis via sister-chromatid exchanges

August 13, 2026| Source: Science

Mammalian cells frequently enter mitosis before DNA replication has finished, necessitating the rapid processing of unreplicated loci to facilitate chromosome segregation. The TRAIP ubiquitin ligase induces replisome disassembly during mitosis, triggering the cleavage of DNA replication forks. Until now, the mechanisms that regulate TRAIP and process cleaved DNA replication forks were unclear. In this study, we show that the transcription termination factor 2 (TTF2) adenosine triphosphatase is a new type of phosphoreceptor that binds a conserved phosphorylation site on TRAIP during mitosis. TTF2 couples phosphorylated TRAIP to DNA polymerase ε (Pol ε) in the replisome, leading TRAIP to ubiquitylate the CDC45-MCM-GINS (CMG) helicase. This triggers mitotic replisome disassembly and a repair pathway that produces sister-chromatid exchanges, supporting a model for how fork cleavage promotes the segregation of underreplicated loci in mammalian cells.

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