Loss of cytoplasmic actin filaments raises nuclear actin levels to drive INO80C-dependent chromosome fragmentation
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...
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Nature Portfolio
2024-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54141-0 |
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| author | Verena Hurst Christian B. Gerhold Cleo V. D. Tarashev Kiran Challa Andrew Seeber Shota Yamazaki Britta Knapp Stephen B. Helliwell Bernd Bodenmiller Masahiko Harata Kenji Shimada Susan M. Gasser |
| author_facet | Verena Hurst Christian B. Gerhold Cleo V. D. Tarashev Kiran Challa Andrew Seeber Shota Yamazaki Britta Knapp Stephen B. Helliwell Bernd Bodenmiller Masahiko Harata Kenji Shimada Susan M. Gasser |
| author_sort | Verena Hurst |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-c6eea7d7981e47d3bf6b2e622889e3f4 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj-art-c6eea7d7981e47d3bf6b2e622889e3f42024-11-17T12:34:59ZengNature PortfolioNature Communications2041-17232024-11-0115112210.1038/s41467-024-54141-0Loss of cytoplasmic actin filaments raises nuclear actin levels to drive INO80C-dependent chromosome fragmentationVerena Hurst0Christian B. Gerhold1Cleo V. D. Tarashev2Kiran Challa3Andrew Seeber4Shota Yamazaki5Britta Knapp6Stephen B. Helliwell7Bernd Bodenmiller8Masahiko Harata9Kenji Shimada10Susan M. Gasser11Friedrich Miescher Institute for Biomedical Research, Fabrikstrasse 24Friedrich Miescher Institute for Biomedical Research, Fabrikstrasse 24Friedrich Miescher Institute for Biomedical Research, Fabrikstrasse 24Friedrich Miescher Institute for Biomedical Research, Fabrikstrasse 24Friedrich Miescher Institute for Biomedical Research, Fabrikstrasse 24Lab. Molecular Biochemistry, Graduate School of Agricultural Science, Tohoku University, Aramaki Aza-Aoba 468-1, Aoba-kuNovartis Institutes for Biomedical Research, Novartis Pharma AG, Fabrikstrasse 22Novartis Institutes for Biomedical Research, Novartis Pharma AG, Fabrikstrasse 22Institute of Molecular Life Sciences, University of Zürich, Winterthurerstrasse 190Lab. Molecular Biochemistry, Graduate School of Agricultural Science, Tohoku University, Aramaki Aza-Aoba 468-1, Aoba-kuFriedrich Miescher Institute for Biomedical Research, Fabrikstrasse 24Friedrich Miescher Institute for Biomedical Research, Fabrikstrasse 24Abstract 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.https://doi.org/10.1038/s41467-024-54141-0 |
| spellingShingle | Verena Hurst Christian B. Gerhold Cleo V. D. Tarashev Kiran Challa Andrew Seeber Shota Yamazaki Britta Knapp Stephen B. Helliwell Bernd Bodenmiller Masahiko Harata Kenji Shimada Susan M. Gasser Loss of cytoplasmic actin filaments raises nuclear actin levels to drive INO80C-dependent chromosome fragmentation Nature Communications |
| title | Loss of cytoplasmic actin filaments raises nuclear actin levels to drive INO80C-dependent chromosome fragmentation |
| title_full | Loss of cytoplasmic actin filaments raises nuclear actin levels to drive INO80C-dependent chromosome fragmentation |
| title_fullStr | Loss of cytoplasmic actin filaments raises nuclear actin levels to drive INO80C-dependent chromosome fragmentation |
| title_full_unstemmed | Loss of cytoplasmic actin filaments raises nuclear actin levels to drive INO80C-dependent chromosome fragmentation |
| title_short | Loss of cytoplasmic actin filaments raises nuclear actin levels to drive INO80C-dependent chromosome fragmentation |
| title_sort | loss of cytoplasmic actin filaments raises nuclear actin levels to drive ino80c dependent chromosome fragmentation |
| url | https://doi.org/10.1038/s41467-024-54141-0 |
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