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.
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1 February 2021
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December 23 2020
An ATM–Chk2–INCENP pathway activates the abscission checkpoint
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Eleni Petsalaki
,
Eleni Petsalaki
Department of Biology, University of Crete, Heraklion, Greece
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George Zachos
Department of Biology, University of Crete, Heraklion, Greece
Correspondence to George Zachos: gzachos@uoc.gr
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Eleni Petsalaki
Department of Biology, University of Crete, Heraklion, Greece
George Zachos
Department of Biology, University of Crete, Heraklion, Greece
Correspondence to George Zachos: gzachos@uoc.gr
Received:
August 07 2020
Revision Received:
October 29 2020
Accepted:
November 23 2020
Online Issn: 1540-8140
Print Issn: 0021-9525
Funding:
State Scholarships Foundation
(MIS-5033021)
© 2020 Petsalaki and Zachos
2020
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/).
J Cell Biol (2021) 220 (2): e202008029.
Article history
Received:
August 07 2020
Revision Received:
October 29 2020
Accepted:
November 23 2020
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Citation
Eleni Petsalaki, George Zachos; An ATM–Chk2–INCENP pathway activates the abscission checkpoint. J Cell Biol 1 February 2021; 220 (2): e202008029. doi: https://doi.org/10.1083/jcb.202008029
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