ATR protects centromere identity by promoting DAXX association with PML nuclear bodies
Summary: Centromere protein A (CENP-A) defines centromere identity and nucleates kinetochore formation for mitotic chromosome segregation. Here, we show that ataxia telangiectasia and Rad3-related (ATR) kinase, a master regulator of the DNA damage response, protects CENP-A occupancy at interphase ce...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-05-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723005065 |
| _version_ | 1797829563498102784 |
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| author | Isabelle Trier Elizabeth M. Black Yoon Ki Joo Lilian Kabeche |
| author_facet | Isabelle Trier Elizabeth M. Black Yoon Ki Joo Lilian Kabeche |
| author_sort | Isabelle Trier |
| collection | DOAJ |
| description | Summary: Centromere protein A (CENP-A) defines centromere identity and nucleates kinetochore formation for mitotic chromosome segregation. Here, we show that ataxia telangiectasia and Rad3-related (ATR) kinase, a master regulator of the DNA damage response, protects CENP-A occupancy at interphase centromeres in a DNA damage-independent manner. In unperturbed cells, ATR localizes to promyelocytic leukemia nuclear bodies (PML NBs), which house the histone H3.3 chaperone DAXX (death domain-associated protein 6). We find that ATR inhibition reduces DAXX association with PML NBs, resulting in the DAXX-dependent loss of CENP-A and an aberrant increase in H3.3 at interphase centromeres. Additionally, we show that ATR-dependent phosphorylation within the C terminus of DAXX regulates CENP-A occupancy at centromeres and DAXX localization. Lastly, we demonstrate that acute ATR inhibition during interphase leads to kinetochore formation defects and an increased rate of lagging chromosomes. These findings highlight a mechanism by which ATR protects centromere identity and genome stability. |
| first_indexed | 2024-04-09T13:22:10Z |
| format | Article |
| id | doaj.art-8a50cbb027794ef0918b632cf7919492 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-09T13:22:10Z |
| publishDate | 2023-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-8a50cbb027794ef0918b632cf79194922023-05-11T04:23:49ZengElsevierCell Reports2211-12472023-05-01425112495ATR protects centromere identity by promoting DAXX association with PML nuclear bodiesIsabelle Trier0Elizabeth M. Black1Yoon Ki Joo2Lilian Kabeche3Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511, USA; Yale Cancer Biology Institute, Yale University, West Haven, CT 06516, USADepartment of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511, USA; Yale Cancer Biology Institute, Yale University, West Haven, CT 06516, USADepartment of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511, USA; Yale Cancer Biology Institute, Yale University, West Haven, CT 06516, USADepartment of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06511, USA; Yale Cancer Biology Institute, Yale University, West Haven, CT 06516, USA; Corresponding authorSummary: Centromere protein A (CENP-A) defines centromere identity and nucleates kinetochore formation for mitotic chromosome segregation. Here, we show that ataxia telangiectasia and Rad3-related (ATR) kinase, a master regulator of the DNA damage response, protects CENP-A occupancy at interphase centromeres in a DNA damage-independent manner. In unperturbed cells, ATR localizes to promyelocytic leukemia nuclear bodies (PML NBs), which house the histone H3.3 chaperone DAXX (death domain-associated protein 6). We find that ATR inhibition reduces DAXX association with PML NBs, resulting in the DAXX-dependent loss of CENP-A and an aberrant increase in H3.3 at interphase centromeres. Additionally, we show that ATR-dependent phosphorylation within the C terminus of DAXX regulates CENP-A occupancy at centromeres and DAXX localization. Lastly, we demonstrate that acute ATR inhibition during interphase leads to kinetochore formation defects and an increased rate of lagging chromosomes. These findings highlight a mechanism by which ATR protects centromere identity and genome stability.http://www.sciencedirect.com/science/article/pii/S2211124723005065CP: Molecular biology |
| spellingShingle | Isabelle Trier Elizabeth M. Black Yoon Ki Joo Lilian Kabeche ATR protects centromere identity by promoting DAXX association with PML nuclear bodies Cell Reports CP: Molecular biology |
| title | ATR protects centromere identity by promoting DAXX association with PML nuclear bodies |
| title_full | ATR protects centromere identity by promoting DAXX association with PML nuclear bodies |
| title_fullStr | ATR protects centromere identity by promoting DAXX association with PML nuclear bodies |
| title_full_unstemmed | ATR protects centromere identity by promoting DAXX association with PML nuclear bodies |
| title_short | ATR protects centromere identity by promoting DAXX association with PML nuclear bodies |
| title_sort | atr protects centromere identity by promoting daxx association with pml nuclear bodies |
| topic | CP: Molecular biology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723005065 |
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