Chk2 sustains PLK1 activity in mitosis to ensure proper chromosome segregation
Abstract Polo-like kinase 1 (PLK1) protects against genome instability by ensuring timely and accurate mitotic cell division, and its activity is tightly regulated throughout the cell cycle. Although the pathways that initially activate PLK1 in G2 are well-characterized, the factors that directly re...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-12-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54922-7 |
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| author | Elizabeth M. Black Carlos Andrés Ramírez Parrado Isabelle Trier Wenxue Li Yoon Ki Joo Jennifer Pichurin Yansheng Liu Lilian Kabeche |
| author_facet | Elizabeth M. Black Carlos Andrés Ramírez Parrado Isabelle Trier Wenxue Li Yoon Ki Joo Jennifer Pichurin Yansheng Liu Lilian Kabeche |
| author_sort | Elizabeth M. Black |
| collection | DOAJ |
| description | Abstract Polo-like kinase 1 (PLK1) protects against genome instability by ensuring timely and accurate mitotic cell division, and its activity is tightly regulated throughout the cell cycle. Although the pathways that initially activate PLK1 in G2 are well-characterized, the factors that directly regulate mitotic PLK1 remain poorly understood. Here, we identify that human PLK1 activity is sustained by the DNA damage response kinase Checkpoint kinase 2 (Chk2) in mitosis. Chk2 directly phosphorylates PLK1 T210, a residue on its T-loop whose phosphorylation is essential for full PLK1 kinase activity. Loss of Chk2-dependent PLK1 activity causes increased mitotic errors, including chromosome misalignment, chromosome missegregation, and cytokinetic defects. Moreover, Chk2 deficiency increases sensitivity to PLK1 inhibitors, suggesting that Chk2 status may be an informative biomarker for PLK1 inhibitor efficacy. This work demonstrates that Chk2 sustains mitotic PLK1 activity and protects genome stability through discrete functions in interphase DNA damage repair and mitotic chromosome segregation. |
| format | Article |
| id | doaj-art-d4d45d17eb6c4cdfb976eba916624502 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-d4d45d17eb6c4cdfb976eba9166245022025-01-05T12:36:15ZengNature PortfolioNature Communications2041-17232024-12-0115111710.1038/s41467-024-54922-7Chk2 sustains PLK1 activity in mitosis to ensure proper chromosome segregationElizabeth M. Black0Carlos Andrés Ramírez Parrado1Isabelle Trier2Wenxue Li3Yoon Ki Joo4Jennifer Pichurin5Yansheng Liu6Lilian Kabeche7Department of Molecular Biophysics and Biochemistry, Yale UniversityDepartment of Molecular Biophysics and Biochemistry, Yale UniversityDepartment of Molecular Biophysics and Biochemistry, Yale UniversityYale Cancer Biology Institute, Yale UniversityDepartment of Molecular Biophysics and Biochemistry, Yale UniversityDepartment of Molecular Biophysics and Biochemistry, Yale UniversityYale Cancer Biology Institute, Yale UniversityDepartment of Molecular Biophysics and Biochemistry, Yale UniversityAbstract Polo-like kinase 1 (PLK1) protects against genome instability by ensuring timely and accurate mitotic cell division, and its activity is tightly regulated throughout the cell cycle. Although the pathways that initially activate PLK1 in G2 are well-characterized, the factors that directly regulate mitotic PLK1 remain poorly understood. Here, we identify that human PLK1 activity is sustained by the DNA damage response kinase Checkpoint kinase 2 (Chk2) in mitosis. Chk2 directly phosphorylates PLK1 T210, a residue on its T-loop whose phosphorylation is essential for full PLK1 kinase activity. Loss of Chk2-dependent PLK1 activity causes increased mitotic errors, including chromosome misalignment, chromosome missegregation, and cytokinetic defects. Moreover, Chk2 deficiency increases sensitivity to PLK1 inhibitors, suggesting that Chk2 status may be an informative biomarker for PLK1 inhibitor efficacy. This work demonstrates that Chk2 sustains mitotic PLK1 activity and protects genome stability through discrete functions in interphase DNA damage repair and mitotic chromosome segregation.https://doi.org/10.1038/s41467-024-54922-7 |
| spellingShingle | Elizabeth M. Black Carlos Andrés Ramírez Parrado Isabelle Trier Wenxue Li Yoon Ki Joo Jennifer Pichurin Yansheng Liu Lilian Kabeche Chk2 sustains PLK1 activity in mitosis to ensure proper chromosome segregation Nature Communications |
| title | Chk2 sustains PLK1 activity in mitosis to ensure proper chromosome segregation |
| title_full | Chk2 sustains PLK1 activity in mitosis to ensure proper chromosome segregation |
| title_fullStr | Chk2 sustains PLK1 activity in mitosis to ensure proper chromosome segregation |
| title_full_unstemmed | Chk2 sustains PLK1 activity in mitosis to ensure proper chromosome segregation |
| title_short | Chk2 sustains PLK1 activity in mitosis to ensure proper chromosome segregation |
| title_sort | chk2 sustains plk1 activity in mitosis to ensure proper chromosome segregation |
| url | https://doi.org/10.1038/s41467-024-54922-7 |
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