Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Petsalaki, Eleni, Zachos, George
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2020
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
_version_ 1783629267067731968
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
work_keys_str_mv AT petsalakieleni anatmchk2incenppathwayactivatestheabscissioncheckpoint
AT zachosgeorge anatmchk2incenppathwayactivatestheabscissioncheckpoint
AT petsalakieleni atmchk2incenppathwayactivatestheabscissioncheckpoint
AT zachosgeorge atmchk2incenppathwayactivatestheabscissioncheckpoint