Loss of cytoplasmic actin filaments raises nuclear actin levels to drive INO80C-dependent chromosome fragmentation

  • Nat Commun. 2024 Nov 15;15(1):9910. doi: 10.1038/s41467-024-54141-0.
Verena Hurst  #  1 ,  Christian B Gerhold  #  1  2 ,  Cleo V D Tarashev  1 ,  Kiran Challa  1  3 ,  Andrew Seeber  1  4 ,  Shota Yamazaki  5 ,  Britta Knapp  6 ,  Stephen B Helliwell  6  7 ,  Bernd Bodenmiller  8 ,  Masahiko Harata  5 ,  Kenji Shimada  1 ,  Susan M Gasser  9  10
Affiliations
  • 1. Friedrich Miescher Institute for Biomedical Research, Fabrikstrasse 24, 4056, Basel, Switzerland.
  • 2. Bühlmann Laboratories AG, Baselstrasse 55, 4124, Schönenbuch, Switzerland.
  • 3. Mechano-Genomic Group, Division of Biology and Chemistry, Paul-Scherrer Institute, Villigen, Switzerland.
  • 4. Transition Bio Inc, 250 Arsenal St, Watertown, 02472, MA, USA.
  • 5. Lab. Molecular Biochemistry, Graduate School of Agricultural Science, Tohoku University, Aramaki Aza-Aoba 468-1, Aoba-ku, Sendai, 980-8572, Japan.
  • 6. Novartis Institutes for Biomedical Research, Novartis Pharma AG, Fabrikstrasse 22, 4056, Basel, Switzerland.
  • 7. Cellvie AG, Zurich, Switzerland.
  • 8. Institute of Molecular Life Sciences, University of Zürich, Winterthurerstrasse 190, 8057, Zürich, Switzerland.
  • 9. Friedrich Miescher Institute for Biomedical Research, Fabrikstrasse 24, 4056, Basel, Switzerland. [email protected].
  • 10. University of Lausanne, Department of Fundamental Microbiology, and Agora Cancer Center, ISREC Foundation, rue du Bugnon 25A, 1005, Lausanne, Switzerland. [email protected].
  • # Contributed equally.
PMID: 39548059 DOI: 10.1038/s41467-024-54141-0
Abstract

Loss of cytosolic actin filaments upon TORC2 inhibition triggers chromosome fragmentation in yeast, which results from altered base excision repair of Zeocin-induced lesions. To find the link between TORC2 kinase and this yeast chromosome shattering (YCS) we performed phosphoproteomics. YCS-relevant phospho-targets included plasma membrane-associated regulators of actin polymerization, such as Las17, the yeast Wiscott-Aldrich Syndrome protein. Induced degradation of Las17 was sufficient to trigger YCS in presence of Zeocin, bypassing TORC2 inhibition. In yeast, Las17 does not act directly at damage, but instead its loss, like TORC2 inhibition, raises nuclear actin levels. Nuclear actin, in complex with Arp4, forms an essential subunit of several nucleosome remodeler complexes, including INO80C, which facilitates DNA Polymerase elongation. Here we show that the genetic ablation of INO80C activity leads to partial YCS resistance, suggesting that elevated levels of nuclear G-actin may stimulate INO80C to increase DNA Polymerase processivity and convert single-strand lesions into double-strand breaks.

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