An Aurora B-RPA signaling axis secures chromosome segregation fidelity
Abstract Errors in chromosome segregation underlie genomic instability associated with cancers. Resolution of replication and recombination intermediates and protection of vulnerable single-stranded DNA (ssDNA) intermediates during mitotic progression requires the ssDNA binding protein Replication P...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-38711-2 |
| _version_ | 1797817913938280448 |
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| author | Poonam Roshan Sahiti Kuppa Jenna R. Mattice Vikas Kaushik Rahul Chadda Nilisha Pokhrel Brunda R. Tumala Aparna Biswas Brian Bothner Edwin Antony Sofia Origanti |
| author_facet | Poonam Roshan Sahiti Kuppa Jenna R. Mattice Vikas Kaushik Rahul Chadda Nilisha Pokhrel Brunda R. Tumala Aparna Biswas Brian Bothner Edwin Antony Sofia Origanti |
| author_sort | Poonam Roshan |
| collection | DOAJ |
| description | Abstract Errors in chromosome segregation underlie genomic instability associated with cancers. Resolution of replication and recombination intermediates and protection of vulnerable single-stranded DNA (ssDNA) intermediates during mitotic progression requires the ssDNA binding protein Replication Protein A (RPA). However, the mechanisms that regulate RPA specifically during unperturbed mitotic progression are poorly resolved. RPA is a heterotrimer composed of RPA70, RPA32 and RPA14 subunits and is predominantly regulated through hyperphosphorylation of RPA32 in response to DNA damage. Here, we have uncovered a mitosis-specific regulation of RPA by Aurora B kinase. Aurora B phosphorylates Ser-384 in the DNA binding domain B of the large RPA70 subunit and highlights a mode of regulation distinct from RPA32. Disruption of Ser-384 phosphorylation in RPA70 leads to defects in chromosome segregation with loss of viability and a feedback modulation of Aurora B activity. Phosphorylation at Ser-384 remodels the protein interaction domains of RPA. Furthermore, phosphorylation impairs RPA binding to DSS1 that likely suppresses homologous recombination during mitosis by preventing recruitment of DSS1-BRCA2 to exposed ssDNA. We showcase a critical Aurora B-RPA signaling axis in mitosis that is essential for maintaining genomic integrity. |
| first_indexed | 2024-03-13T09:00:30Z |
| format | Article |
| id | doaj.art-65036afea1644453947715d045612938 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-13T09:00:30Z |
| publishDate | 2023-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-65036afea1644453947715d0456129382023-05-28T11:21:36ZengNature PortfolioNature Communications2041-17232023-05-0114111910.1038/s41467-023-38711-2An Aurora B-RPA signaling axis secures chromosome segregation fidelityPoonam Roshan0Sahiti Kuppa1Jenna R. Mattice2Vikas Kaushik3Rahul Chadda4Nilisha Pokhrel5Brunda R. Tumala6Aparna Biswas7Brian Bothner8Edwin Antony9Sofia Origanti10Department of Biology, St. Louis UniversityDepartment of Biochemistry and Molecular Biology, St. Louis University School of MedicineDepartment of Biochemistry, Montana State UniversityDepartment of Biochemistry and Molecular Biology, St. Louis University School of MedicineDepartment of Biochemistry and Molecular Biology, St. Louis University School of MedicineDepartment of Biological Sciences, Marquette UniversityDepartment of Biochemistry and Molecular Biology, St. Louis University School of MedicineDepartment of Biology, St. Louis UniversityDepartment of Biochemistry, Montana State UniversityDepartment of Biochemistry and Molecular Biology, St. Louis University School of MedicineDepartment of Biology, St. Louis UniversityAbstract Errors in chromosome segregation underlie genomic instability associated with cancers. Resolution of replication and recombination intermediates and protection of vulnerable single-stranded DNA (ssDNA) intermediates during mitotic progression requires the ssDNA binding protein Replication Protein A (RPA). However, the mechanisms that regulate RPA specifically during unperturbed mitotic progression are poorly resolved. RPA is a heterotrimer composed of RPA70, RPA32 and RPA14 subunits and is predominantly regulated through hyperphosphorylation of RPA32 in response to DNA damage. Here, we have uncovered a mitosis-specific regulation of RPA by Aurora B kinase. Aurora B phosphorylates Ser-384 in the DNA binding domain B of the large RPA70 subunit and highlights a mode of regulation distinct from RPA32. Disruption of Ser-384 phosphorylation in RPA70 leads to defects in chromosome segregation with loss of viability and a feedback modulation of Aurora B activity. Phosphorylation at Ser-384 remodels the protein interaction domains of RPA. Furthermore, phosphorylation impairs RPA binding to DSS1 that likely suppresses homologous recombination during mitosis by preventing recruitment of DSS1-BRCA2 to exposed ssDNA. We showcase a critical Aurora B-RPA signaling axis in mitosis that is essential for maintaining genomic integrity.https://doi.org/10.1038/s41467-023-38711-2 |
| spellingShingle | Poonam Roshan Sahiti Kuppa Jenna R. Mattice Vikas Kaushik Rahul Chadda Nilisha Pokhrel Brunda R. Tumala Aparna Biswas Brian Bothner Edwin Antony Sofia Origanti An Aurora B-RPA signaling axis secures chromosome segregation fidelity Nature Communications |
| title | An Aurora B-RPA signaling axis secures chromosome segregation fidelity |
| title_full | An Aurora B-RPA signaling axis secures chromosome segregation fidelity |
| title_fullStr | An Aurora B-RPA signaling axis secures chromosome segregation fidelity |
| title_full_unstemmed | An Aurora B-RPA signaling axis secures chromosome segregation fidelity |
| title_short | An Aurora B-RPA signaling axis secures chromosome segregation fidelity |
| title_sort | aurora b rpa signaling axis secures chromosome segregation fidelity |
| url | https://doi.org/10.1038/s41467-023-38711-2 |
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