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

TY - JOUR

T1 - TTF2 processes sites of incomplete DNA replication during mitosis via sister-chromatid exchanges

AU - Fujisawa, Ryo

AU - Labib, Karim P. M.

PY - 2026/8/13

Y1 - 2026/8/13

N2 - 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.

AB - 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.

KW - Animals

KW - Humans

KW - Cell Cycle Proteins/metabolism

KW - Chromosome Segregation

KW - DNA Polymerase II/metabolism

KW - DNA Replication

KW - DNA-Binding Proteins/metabolism

KW - Mitosis

KW - Phosphorylation

KW - Sister Chromatid Exchange

KW - Ubiquitin-Protein Ligases/metabolism

KW - Ubiquitination

KW - Mice

KW - Cell Line, Tumor

KW - Adenosine Triphosphatases/metabolism

KW - Transcription Factors

KW - Replisomes/metabolism

UR - https://www.scopus.com/pages/publications/105047504193

U2 - 10.1126/science.aeh2300

DO - 10.1126/science.aeh2300

M3 - Article

C2 - 42391325

SN - 0036-8075

VL - 393

SP - eaeh2300

JO - Science

JF - Science

IS - 6812

ER -