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

Schalbetter, Stephanie, Mansoubi, Sahar, Chambers, Anna L., Downs, Jessica and Baxter, Jon (2015) Fork rotation and DNA precatenation are restricted during DNA replication to prevent chromosomal instability. PNAS.

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Abstract

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.

Item Type: Article
Keywords: DNA replication | topoisomerases | DNA topology | forkrotation | DNA catenation
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Subjects: Q Science > QD Chemistry > QD0241 Organic chemistry > QD0415 Biochemistry
Depositing User: Gee Wheatley
Date Deposited: 13 Aug 2015 09:37
Last Modified: 12 Sep 2017 01:24
URI: http://sro.sussex.ac.uk/id/eprint/56104

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