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Separable functions of Tof1/Timeless in intra-S-checkpoint signalling, replisome stability and DNA topological stress

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Version 2 2023-06-12, 09:32
Version 1 2023-06-09, 21:51
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posted on 2023-06-12, 09:32 authored by Emma Westhorpe, Andrea KeszthelyiAndrea Keszthelyi, Nicola Minchell, David JonesDavid Jones, Jon BaxterJon Baxter
The highly conserved Tof1/Timeless proteins minimise replication stress and promote normal DNA replication. They are required to mediate the DNA replication checkpoint (DRC), the stable pausing of forks at protein fork blocks, the coupling of DNA helicase and polymerase functions during replication stress (RS) and the preferential resolution of DNA topological stress ahead of the fork. Here we demonstrate that the roles of the Saccharomyces cerevisiae Timeless protein Tof1 in DRC signalling and resolution of DNA topological stress require distinct N and C terminal regions of the protein, whereas the other functions of Tof1 are closely linked to the stable interaction between Tof1 and its constitutive binding partner Csm3/Tipin. By separating the role of Tof1 in DRC from fork stabilisation and coupling, we show that Tof1 has distinct activities in checkpoint activation and replisome stability to ensure the viable completion of DNA replication following replication stress.

Funding

Investigating how replication fork rotation causes chromosomal instability during S phase; G1903; BBSRC-BIOTECHNOLOGY & BIOLOGICAL SCIENCES RESEARCH COUNCIL; BB/N007344/1

History

Publication status

  • Published

File Version

  • Published version

Journal

Nucleic Acids Research

ISSN

0305-1048

Publisher

Oxford University Press

Issue

21

Volume

48

Page range

12169-12187

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2020-10-12

First Open Access (FOA) Date

2020-11-12

First Compliant Deposit (FCD) Date

2020-10-09

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