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bioRxiv · 10.1101/2024.12.01.626218

TTF2 drives mitotic replisome disassembly and MiDAS by coupling the TRAIP ubiquitin ligase to Pol epsilon

FUJISAWA, R.·Labib, K. P. M.
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Abstract

Mammalian cells frequently enter mitosis before DNA replication has finished, necessitating the rapid processing of replication forks to facilitate chromosome segregation. The TRAIP ubiquitin ligase induces mitotic replisome disassembly, fork cleavage, and repair via Mitotic DNA Synthesis (MiDAS). Until now, it was unclear how TRAIP is regulated in mitotic cells. Here we show that TRAIP phosphorylation mediates a complex with the TTF2 ATPase and DNA Polymerase {varepsilon} (Pol{varepsilon}). Whereas TTF2 ATPase activity removes RNA polymerase II from mitotic chromosomes, replisome disassembly involves an unanticipated mechanism. The TTF2 amino terminus couples TRAIP to Pol{varepsilon}, via tandem Zinc fingers that recognise phosphorylated TRAIP, and a motif that binds to POLE2. Thereby, TTF2 and Pol{varepsilon} cause TRAIP to ubiquitylate the CDC45-MCM-GINS (CMG) helicase, triggering replisome disassembly and MiDAS. These data identify TTF2 as a multifunctional regulator of chromatin transactions during mitosis.

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FUJISAWA, R., Labib, K. P. M.. 2024-12-02. TTF2 drives mitotic replisome disassembly and MiDAS by coupling the TRAIP ubiquitin ligase to Pol epsilon. https://doi.org/10.1101/2024.12.01.626218

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