University of Sussex
Browse
1/1
2 files

Fork rotation and DNA precatenation are restricted during DNA replication to prevent chromosomal instability

journal contribution
posted on 2023-06-08, 22:07 authored by Stephanie A Schalbetter, Sahar Mansoubi, Anna L Chambers, Jessica A Downs, Jon BaxterJon Baxter
Faithful genome duplication and inheritance require the complete resolution of all intertwines within the parental DNA duplex. This is achieved by topoisomerase action ahead of the replication fork or by fork rotation and subsequent resolution of the DNA precatenation formed. Although fork rotation predominates at replication termination, in vitro studies have suggested that it also occurs frequently during elongation. However, the factors that influence fork rotation and how rotation and precatenation may influence other replication-associated processes are unknown. Here we analyze the causes and consequences of fork rotation in budding yeast. We find that fork rotation and precatenation preferentially occur in contexts that inhibit topoisomerase action ahead of the fork, including stable protein–DNA fragile sites and termination. However, generally, fork rotation and precatenation are actively inhibited by Timeless/Tof1 and Tipin/Csm3. In the absence of Tof1/Timeless, excessive fork rotation and precatenation cause extensive DNA damage following DNA replication. With Tof1, damage related to precatenation is focused on the fragile protein–DNA sites where fork rotation is induced. We conclude that although fork rotation and precatenation facilitate unwinding in hard-to-replicate contexts, they intrinsically disrupt normal chromosome duplication and are therefore restricted by Timeless/Tipin.

History

Publication status

  • Published

File Version

  • Published version

Journal

Proceedings of the National Academy of Sciences

ISSN

0027-8424

Publisher

National Academy of Sciences

Issue

33

Volume

112

Article number

E4565-E4570

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2015-08-13

First Open Access (FOA) Date

2021-03-09

First Compliant Deposit (FCD) Date

2021-03-09

Usage metrics

    University of Sussex (Publications)

    Categories

    No categories selected

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC