TORC2 inhibition triggers yeast chromosome fragmentation through misregulated Base Excision Repair of clustered oxidation events

  • Nat Commun. 2024 Nov 15;15(1):9908. doi: 10.1038/s41467-024-54142-z.
Kenji Shimada  1 ,  Cleo V D Tarashev  1  2 ,  Stephanie Bregenhorn  3 ,  Christian B Gerhold  1  4 ,  Barbara van Loon  5 ,  Gregory Roth  1 ,  Verena Hurst  1 ,  Josef Jiricny  3 ,  Stephen B Helliwell  6  7 ,  Susan M Gasser  8  9
Affiliations
  • 1. Friedrich Miescher Institute for Biomedical Research, Fabrikstrasse 24, Basel, Switzerland.
  • 2. Dynamics Group AG., Av. de Rumine 5, Lausanne, Switzerland.
  • 3. Institute of Molecular Life Sciences, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland; and Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland.
  • 4. BÜHLMANN Laboratories AG, Baselstrasse 55, Schönenbuch, Switzerland.
  • 5. Norwegian University of Science and Technology; Department of Clinical and Molecular Medicine, Erling Skjalgssonsgatan, Trondheim, Norway.
  • 6. Novartis Institutes of Biomedical Research, Novartis Intl. AG, Basel, Switzerland.
  • 7. Cellvie AG, Zurich, Switzerland.
  • 8. Friedrich Miescher Institute for Biomedical Research, Fabrikstrasse 24, Basel, Switzerland. [email protected].
  • 9. University of Lausanne, Department of Fundamental Microbiology, and Agora Cancer Center, ISREC Foundation, rue du Bugnon 25A, Lausanne, Switzerland. [email protected].
PMID: 39548071 DOI: 10.1038/s41467-024-54142-z
Abstract

Combinational therapies provoking cell death are of major interest in oncology. Combining TORC2 kinase inhibition with the radiomimetic drug Zeocin results in a rapid accumulation of double-strand breaks (DSB) in the budding yeast genome. This lethal Yeast Chromosome Shattering (YCS) requires conserved Enzymes of base excision repair. YCS can be attenuated by eliminating three N-glycosylases or endonucleases Apn1/Apn2 and Rad1, which act to convert oxidized Bases into abasic sites and single-strand nicks. Adjacent lesions must be repaired in a step-wise fashion to avoid generating DSBs. Artificially increasing nuclear actin by destabilizing cytoplasmic actin filaments or by expressing a nuclear export-deficient actin interferes with this step-wise repair and generates DSBs, while mutants that impair DNA Polymerase processivity reduce them. Repair factors that bind actin include Apn1, RFA and the actin-dependent chromatin remodeler INO80C. During YCS, increased INO80C activity could enhance both DNA Polymerase processivity and repair factor access to convert clustered lesions into DSBs.

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