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The CIP2A-TOPBP1 complex safeguards chromosomal stability during mitosis
The accurate repair of DNA double-strand breaks (DSBs), highly toxic DNA lesions, is crucial for genome integrity and is tightly regulated during the cell cycle. In mitosis, cells inactivate DSB repair in favor of a tethering mechanism that stabilizes broken chromosomes until they are repaired in th...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9288427/ https://www.ncbi.nlm.nih.gov/pubmed/35842428 http://dx.doi.org/10.1038/s41467-022-31865-5 |
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author | De Marco Zompit, Mara Esteban, Mònica Torres Mooser, Clémence Adam, Salomé Rossi, Silvia Emma Jeanrenaud, Alain Leimbacher, Pia-Amata Fink, Daniel Shorrocks, Ann-Marie K. Blackford, Andrew N. Durocher, Daniel Stucki, Manuel |
author_facet | De Marco Zompit, Mara Esteban, Mònica Torres Mooser, Clémence Adam, Salomé Rossi, Silvia Emma Jeanrenaud, Alain Leimbacher, Pia-Amata Fink, Daniel Shorrocks, Ann-Marie K. Blackford, Andrew N. Durocher, Daniel Stucki, Manuel |
author_sort | De Marco Zompit, Mara |
collection | PubMed |
description | The accurate repair of DNA double-strand breaks (DSBs), highly toxic DNA lesions, is crucial for genome integrity and is tightly regulated during the cell cycle. In mitosis, cells inactivate DSB repair in favor of a tethering mechanism that stabilizes broken chromosomes until they are repaired in the subsequent cell cycle phases. How this is achieved mechanistically is not yet understood, but the adaptor protein TOPBP1 is critically implicated in this process. Here, we identify CIP2A as a TOPBP1-interacting protein that regulates TOPBP1 localization specifically in mitosis. Cells lacking CIP2A display increased radio-sensitivity, micronuclei formation and chromosomal instability. CIP2A is actively exported from the cell nucleus in interphase but, upon nuclear envelope breakdown at the onset of mitosis, gains access to chromatin where it forms a complex with MDC1 and TOPBP1 to promote TOPBP1 recruitment to sites of mitotic DSBs. Collectively, our data uncover CIP2A-TOPBP1 as a mitosis-specific genome maintenance complex. |
format | Online Article Text |
id | pubmed-9288427 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-92884272022-07-18 The CIP2A-TOPBP1 complex safeguards chromosomal stability during mitosis De Marco Zompit, Mara Esteban, Mònica Torres Mooser, Clémence Adam, Salomé Rossi, Silvia Emma Jeanrenaud, Alain Leimbacher, Pia-Amata Fink, Daniel Shorrocks, Ann-Marie K. Blackford, Andrew N. Durocher, Daniel Stucki, Manuel Nat Commun Article The accurate repair of DNA double-strand breaks (DSBs), highly toxic DNA lesions, is crucial for genome integrity and is tightly regulated during the cell cycle. In mitosis, cells inactivate DSB repair in favor of a tethering mechanism that stabilizes broken chromosomes until they are repaired in the subsequent cell cycle phases. How this is achieved mechanistically is not yet understood, but the adaptor protein TOPBP1 is critically implicated in this process. Here, we identify CIP2A as a TOPBP1-interacting protein that regulates TOPBP1 localization specifically in mitosis. Cells lacking CIP2A display increased radio-sensitivity, micronuclei formation and chromosomal instability. CIP2A is actively exported from the cell nucleus in interphase but, upon nuclear envelope breakdown at the onset of mitosis, gains access to chromatin where it forms a complex with MDC1 and TOPBP1 to promote TOPBP1 recruitment to sites of mitotic DSBs. Collectively, our data uncover CIP2A-TOPBP1 as a mitosis-specific genome maintenance complex. Nature Publishing Group UK 2022-07-16 /pmc/articles/PMC9288427/ /pubmed/35842428 http://dx.doi.org/10.1038/s41467-022-31865-5 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article De Marco Zompit, Mara Esteban, Mònica Torres Mooser, Clémence Adam, Salomé Rossi, Silvia Emma Jeanrenaud, Alain Leimbacher, Pia-Amata Fink, Daniel Shorrocks, Ann-Marie K. Blackford, Andrew N. Durocher, Daniel Stucki, Manuel The CIP2A-TOPBP1 complex safeguards chromosomal stability during mitosis |
title | The CIP2A-TOPBP1 complex safeguards chromosomal stability during mitosis |
title_full | The CIP2A-TOPBP1 complex safeguards chromosomal stability during mitosis |
title_fullStr | The CIP2A-TOPBP1 complex safeguards chromosomal stability during mitosis |
title_full_unstemmed | The CIP2A-TOPBP1 complex safeguards chromosomal stability during mitosis |
title_short | The CIP2A-TOPBP1 complex safeguards chromosomal stability during mitosis |
title_sort | cip2a-topbp1 complex safeguards chromosomal stability during mitosis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9288427/ https://www.ncbi.nlm.nih.gov/pubmed/35842428 http://dx.doi.org/10.1038/s41467-022-31865-5 |
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