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Uncoordinated long-patch base excision repair at juxtaposed DNA lesions generates a lethal accumulation of double-strand breaks

Kenji Shimada, View ORCID ProfileBarbara van Loon, Christian B. Gerhold, Stephanie Bregenhorn, Verena Hurst, Gregory Roth, Cleo Tarashev, Christian Heinis, Josef Jiricny, Susan M. Gasser
doi: https://doi.org/10.1101/2020.11.15.383513
Kenji Shimada
1Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland
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Barbara van Loon
2; Norwegian University of Science and Technology; Department of Clinical and Molecular Medicine, Erling Skjalgssonsgatan; NO-7491 Trondheim Norway
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  • ORCID record for Barbara van Loon
  • For correspondence: barbara.v.loon@ntnu.no
Christian B. Gerhold
1Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland
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Stephanie Bregenhorn
3; Institute of Molecular Life Sciences, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland; and Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland
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  • For correspondence: jjiricny@ethz.ch
Verena Hurst
1Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland
5Faculty of Natural Sciences, University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland
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Gregory Roth
1Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland
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Cleo Tarashev
1Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland
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Christian Heinis
4; EPFL, Laboratory of Therapeutic Proteins and Peptides, Batochime UNIL, Av. F.-A. Forel 2, CH-1015 Lausanne, Switzerland
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  • For correspondence: christian.heinis@epfl.ch
Josef Jiricny
3; Institute of Molecular Life Sciences, University of Zürich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland; and Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland
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  • For correspondence: jjiricny@ethz.ch
Susan M. Gasser
1Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland
5Faculty of Natural Sciences, University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland
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  • For correspondence: susan.gasser@fmi.ch
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Summary

Inhibition of the TOR pathway (TORC2, or Ypk1/2), or the depolymerization of actin filaments results in catastrophic fragmentation of the yeast genome upon exposure to low doses of the radiomimetic drug Zeocin. We find that the accumulation of double-strand breaks (DSB) is not due to altered DSB repair, but by the uncoordinated activity of base excision repair (BER) at Zeocin-modified DNA bases. We inhibit DSB formation by eliminating glycosylases and/or the endonucleases Apn1/2 and Rad1, implicating these conserved BER enzymes, or events downstream of them, in the conversion of base damage into DSBs. Among DNA polymerases, the reduction of Pol δ, and to a lesser extent Pol ε and Trf4 (a Pol β-like polymerase), reduces DSB formation. Finally, the BER enzymes, Ogg1 and AP endonuclease, are shown to co-precipitate with actin from yeast extracts and as purified proteins, suggesting that actin may interfere directly with the repair of Zeocin-induced damage.

Competing Interest Statement

The authors have declared no competing interest.

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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 November 15, 2020.
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Uncoordinated long-patch base excision repair at juxtaposed DNA lesions generates a lethal accumulation of double-strand breaks
Kenji Shimada, Barbara van Loon, Christian B. Gerhold, Stephanie Bregenhorn, Verena Hurst, Gregory Roth, Cleo Tarashev, Christian Heinis, Josef Jiricny, Susan M. Gasser
bioRxiv 2020.11.15.383513; doi: https://doi.org/10.1101/2020.11.15.383513
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Uncoordinated long-patch base excision repair at juxtaposed DNA lesions generates a lethal accumulation of double-strand breaks
Kenji Shimada, Barbara van Loon, Christian B. Gerhold, Stephanie Bregenhorn, Verena Hurst, Gregory Roth, Cleo Tarashev, Christian Heinis, Josef Jiricny, Susan M. Gasser
bioRxiv 2020.11.15.383513; doi: https://doi.org/10.1101/2020.11.15.383513

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