Yeast centrosomes act as organizing centers to promote Polo kinase-mediated adaptation to persistent DNA damage

• 成果类型: Article
• 署名作者: Langlois-Lemay, Laurence; D'Amours, Damien
• 署名单位: University of Ottawa
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13556
• DOI: 10.1073/pnas.2414426122
• 发表日期: 2025-07-08
• 关键词: double-strand break; budding yeast; genomic instability; spindle orientation; protein-kinase; cell-division; checkpoint; localization; cycle; cdc5

摘要

The ability of cells to overcome cell cycle arrest and adapt to the presence of unrepairable DNA damage is under the control of Polo-like kinases (PLKs) in eukaryotes. How DNA damage checkpoints are silenced or bypassed during the adaptation response is unknown, but the process requires enrichment of the Cdc5 PLK to microtubule organizing centers (MTOCs), such as the yeast centrosomes or spindle pole bodies (SPBs). Here, we found that SPBs play an active role as supramolecular organizing centers that coordinate Cdc5 recruitment and signaling to downstream effectors during the adaptation response DNA damage. We show that SPB components Nud1, Spc110, and Spc72 are key effectors of Cdc5 recruitment to SPBs in the presence of sustained DNA damage. Following recruitment, Cdc5 transduces a phosphosignal to key structural subunits of the SPB, including Cnm67 and Mps3. We demonstrate these phosphorylation events are required to bypass cell cycle checkpoint arrest and enable effective adaptation to DNA damage. This response is specific because it cannot be recapitulated by a generic inactivation MTOC activity. Collectively, our results indicate that centrosomes can act as supramolecular platforms to coordinate dynamic recruitment and substrate selection of PLKs during the DNA damage response (DDR).