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

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Udgivet i:bioRxiv (Dec 2, 2024)
Hovedforfatter: Fujisawa, Ryo
Andre forfattere: Labib, Karim P M
Udgivet:
Cold Spring Harbor Laboratory Press
Fag:
RNA polymerase
DNA biosynthesis
Phosphorylation
Chromosomes
DNA repair
Mammalian cells
Zinc finger proteins
Ubiquitin-protein ligase
Replication forks
Chromatin remodeling
DNA-directed DNA polymerase
Yeast
Mitosis
DNA-directed RNA polymerase
Cdc45 protein
DNA helicase
Cell division
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Resumen: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 epsilon (Pol epsilon). 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 epsilon, via tandem Zinc fingers that recognise phosphorylated TRAIP, and a motif that binds to POLE2. Thereby, TTF2 and Pol epsilon 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.Competing Interest StatementThe authors have declared no competing interest.
ISSN:2692-8205
DOI:10.1101/2024.12.01.626218
Fuente:Biological Science Database