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An ATM–Chk2–INCENP pathway activates the abscission checkpoint
During cell division, in response to chromatin bridges, the chromosomal passenger complex (CPC) delays abscission to prevent chromosome breakage or tetraploidization. Here, we show that inhibition of ATM or Chk2 kinases impairs CPC localization to the midbody center, accelerates midbody resolution i...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Rockefeller University Press
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769160/ https://www.ncbi.nlm.nih.gov/pubmed/33355621 http://dx.doi.org/10.1083/jcb.202008029 |
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author | Petsalaki, Eleni Zachos, George |
author_facet | Petsalaki, Eleni Zachos, George |
author_sort | Petsalaki, Eleni |
collection | PubMed |
description | During cell division, in response to chromatin bridges, the chromosomal passenger complex (CPC) delays abscission to prevent chromosome breakage or tetraploidization. Here, we show that inhibition of ATM or Chk2 kinases impairs CPC localization to the midbody center, accelerates midbody resolution in normally segregating cells, and correlates with premature abscission and chromatin breakage in cytokinesis with trapped chromatin. In cultured human cells, ATM activates Chk2 at late midbodies. In turn, Chk2 phosphorylates human INCENP-Ser91 to promote INCENP binding to Mklp2 kinesin and CPC localization to the midbody center through Mklp2 association with Cep55. Expression of truncated Mklp2 that does not bind to Cep55 or nonphosphorylatable INCENP-Ser91A impairs CPC midbody localization and accelerates abscission. In contrast, expression of phosphomimetic INCENP-Ser91D or a chimeric INCENP protein that is targeted to the midbody center rescues the abscission delay in Chk2-deficient or ATM-deficient cells. Furthermore, the Mre11–Rad50–Nbs1 complex is required for ATM activation at the midbody in cytokinesis with chromatin bridges. These results identify an ATM–Chk2–INCENP pathway that imposes the abscission checkpoint by regulating CPC midbody localization. |
format | Online Article Text |
id | pubmed-7769160 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-77691602021-08-01 An ATM–Chk2–INCENP pathway activates the abscission checkpoint Petsalaki, Eleni Zachos, George J Cell Biol Article During cell division, in response to chromatin bridges, the chromosomal passenger complex (CPC) delays abscission to prevent chromosome breakage or tetraploidization. Here, we show that inhibition of ATM or Chk2 kinases impairs CPC localization to the midbody center, accelerates midbody resolution in normally segregating cells, and correlates with premature abscission and chromatin breakage in cytokinesis with trapped chromatin. In cultured human cells, ATM activates Chk2 at late midbodies. In turn, Chk2 phosphorylates human INCENP-Ser91 to promote INCENP binding to Mklp2 kinesin and CPC localization to the midbody center through Mklp2 association with Cep55. Expression of truncated Mklp2 that does not bind to Cep55 or nonphosphorylatable INCENP-Ser91A impairs CPC midbody localization and accelerates abscission. In contrast, expression of phosphomimetic INCENP-Ser91D or a chimeric INCENP protein that is targeted to the midbody center rescues the abscission delay in Chk2-deficient or ATM-deficient cells. Furthermore, the Mre11–Rad50–Nbs1 complex is required for ATM activation at the midbody in cytokinesis with chromatin bridges. These results identify an ATM–Chk2–INCENP pathway that imposes the abscission checkpoint by regulating CPC midbody localization. Rockefeller University Press 2020-12-23 /pmc/articles/PMC7769160/ /pubmed/33355621 http://dx.doi.org/10.1083/jcb.202008029 Text en © 2020 Petsalaki and Zachos http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Article Petsalaki, Eleni Zachos, George An ATM–Chk2–INCENP pathway activates the abscission checkpoint |
title | An ATM–Chk2–INCENP pathway activates the abscission checkpoint |
title_full | An ATM–Chk2–INCENP pathway activates the abscission checkpoint |
title_fullStr | An ATM–Chk2–INCENP pathway activates the abscission checkpoint |
title_full_unstemmed | An ATM–Chk2–INCENP pathway activates the abscission checkpoint |
title_short | An ATM–Chk2–INCENP pathway activates the abscission checkpoint |
title_sort | atm–chk2–incenp pathway activates the abscission checkpoint |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769160/ https://www.ncbi.nlm.nih.gov/pubmed/33355621 http://dx.doi.org/10.1083/jcb.202008029 |
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