Fork pausing complex engages topoisomerases at the replisome

Replication forks temporarily or terminally pause at hundreds of hard-to-replicate regions around the genome. A conserved pair of budding yeast replisome components Tof1-Csm3 (fission yeast Swi1-Swi3 and human TIMELESS-TIPIN) act as a "molecular brake" and promote fork slowdown at proteina...

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Bibliographic Details
Published in:Genes & development 2020-01, Vol.34 (1-2), p.87-98
Main Authors: Shyian, Maksym, Albert, Benjamin, Zupan, Andreja Moset, Ivanitsa, Vitalii, Charbonnet, Gabriel, Dilg, Daniel, Shore, David
Format: Article
Language:English
Subjects:
Cell Cycle Proteins - metabolism
DNA Helicases - metabolism
DNA Replication - genetics
DNA Topoisomerases - metabolism
DNA Topoisomerases, Type I - metabolism
DNA-Binding Proteins - metabolism
Mutation
Protein Transport
Research Paper
Saccharomyces cerevisiae - genetics
Saccharomyces cerevisiae - metabolism
Saccharomyces cerevisiae Proteins - genetics
Saccharomyces cerevisiae Proteins - metabolism
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Summary:Replication forks temporarily or terminally pause at hundreds of hard-to-replicate regions around the genome. A conserved pair of budding yeast replisome components Tof1-Csm3 (fission yeast Swi1-Swi3 and human TIMELESS-TIPIN) act as a "molecular brake" and promote fork slowdown at proteinaceous replication fork barriers (RFBs), while the accessory helicase Rrm3 assists the replisome in removing protein obstacles. Here we show that the Tof1-Csm3 complex promotes fork pausing independently of Rrm3 helicase by recruiting topoisomerase I (Top1) to the replisome. Topoisomerase II (Top2) partially compensates for the pausing decrease in cells when Top1 is lost from the replisome. The C terminus of Tof1 is specifically required for Top1 recruitment to the replisome and fork pausing but not for DNA replication checkpoint (DRC) activation. We propose that forks pause at proteinaceous RFBs through a "sTOP" mechanism ("slowing down with topoisomerases I-II"), which we show also contributes to protecting cells from topoisomerase-blocking agents.
ISSN:0890-9369
1549-5477
DOI:10.1101/gad.331868.119