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RTEL1 and MCM10 overcome topological stress during vertebrate replication termination

Lillian V. Campos, Briana H. Greer, Darren R. Heintzman, Tamar Kavlashvili, W. Hayes McDonald, Kristie Lindsey Rose, Brandt F. Eichman, View ORCID ProfileJames M. Dewar
doi: https://doi.org/10.1101/2022.01.27.478093
Lillian V. Campos
1Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
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Briana H. Greer
2Department of Biological Sciences and Center for Structural Biology, Vanderbilt University, Nashville, TN 37232, USA
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Darren R. Heintzman
1Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
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Tamar Kavlashvili
1Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
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W. Hayes McDonald
3Department of Biochemistry and Mass Spectrometry Research Center, Vanderbilt University, Nashville, TN 37232, USA
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Kristie Lindsey Rose
3Department of Biochemistry and Mass Spectrometry Research Center, Vanderbilt University, Nashville, TN 37232, USA
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Brandt F. Eichman
2Department of Biological Sciences and Center for Structural Biology, Vanderbilt University, Nashville, TN 37232, USA
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James M. Dewar
1Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
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  • ORCID record for James M. Dewar
  • For correspondence: James.Dewar@vanderbilt.edu
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ABSTRACT

Topological stress can cause replication forks to stall as they converge upon one another during termination of vertebrate DNA synthesis. However, replication forks ultimately overcome topological stress and complete DNA synthesis, suggesting that alternative mechanisms can overcome topological stress. We performed a proteomic analysis of converging replication forks that were stalled by topological stress in Xenopus egg extracts. We found that the helicase RTEL1 and the replisome protein MCM10 were highly enriched on DNA under these conditions. We show that RTEL1 normally plays a minor role during fork convergence while the role of MCM10 is normally negligible. However, RTEL1 and MCM10 both become crucially important for fork convergence under conditions of topological stress. RTEL1 and MCM10 exert non-additive effects on fork convergence and physically interact, suggesting that they function together. Furthermore, RTEL1 and MCM10 do not impact topoisomerase activity but do promote fork progression through a replication barrier. Thus, RTEL1 and MCM10 appear to play a general role in promoting progression of stalled forks, including when forks stall during termination. Overall, our data identify an alternate mechanism of termination involving RTEL1 and MCM10 that can be used to complete DNA synthesis under conditions of topological stress.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • The manuscript has been revised to include funding information in the acknowledgements.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted April 29, 2022.
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RTEL1 and MCM10 overcome topological stress during vertebrate replication termination
Lillian V. Campos, Briana H. Greer, Darren R. Heintzman, Tamar Kavlashvili, W. Hayes McDonald, Kristie Lindsey Rose, Brandt F. Eichman, James M. Dewar
bioRxiv 2022.01.27.478093; doi: https://doi.org/10.1101/2022.01.27.478093
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RTEL1 and MCM10 overcome topological stress during vertebrate replication termination
Lillian V. Campos, Briana H. Greer, Darren R. Heintzman, Tamar Kavlashvili, W. Hayes McDonald, Kristie Lindsey Rose, Brandt F. Eichman, James M. Dewar
bioRxiv 2022.01.27.478093; doi: https://doi.org/10.1101/2022.01.27.478093

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