Sustained CHK2 activity, but not ATM activity, is critical to maintain a G1 arrest after DNA damage in untransformed cells

BACKGROUND: The G1 checkpoint is a critical regulator of genomic stability in untransformed cells, preventing cell cycle progression after DNA damage. DNA double-strand breaks (DSBs) recruit and activate ATM, a kinase which in turn activates the CHK2 kinase to establish G1 arrest. While the onset of...

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Autores: García Santisteban, Iraia, Llopis, Alba, Krenning, Lenno, Vallejo Rodríguez, Jon, Van den Broek, Bram, Zubiaga Elordieta, Ana María, Medem, René H.
Tipo de recurso: artículo
Fecha de publicación:2021
País:España
Institución:Universidad del País Vasco
Repositorio:Addi. Archivo Digital para la Docencia y la Investigación
OAI Identifier:oai:addi.ehu.eus:10810/50544
Acceso en línea:http://hdl.handle.net/10810/50544
Access Level:acceso abierto
Palabra clave:ATM
CHK2
DNA damage
G1 checkpoint
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spelling Sustained CHK2 activity, but not ATM activity, is critical to maintain a G1 arrest after DNA damage in untransformed cellsGarcía Santisteban, IraiaLlopis, AlbaKrenning, LennoVallejo Rodríguez, JonVan den Broek, BramZubiaga Elordieta, Ana MaríaMedem, René H.ATMCHK2DNA damageG1 checkpointBACKGROUND: The G1 checkpoint is a critical regulator of genomic stability in untransformed cells, preventing cell cycle progression after DNA damage. DNA double-strand breaks (DSBs) recruit and activate ATM, a kinase which in turn activates the CHK2 kinase to establish G1 arrest. While the onset of G1 arrest is well understood, the specific role that ATM and CHK2 play in regulating G1 checkpoint maintenance remains poorly characterized. RESULTS: Here we examine the impact of ATM and CHK2 activities on G1 checkpoint maintenance in untransformed cells after DNA damage caused by DSBs. We show that ATM becomes dispensable for G1 checkpoint maintenance as early as 1h after DSB induction. In contrast, CHK2 kinase activity is necessary to maintain the G1 arrest, independently of ATM, ATR, and DNA-PKcs, implying that the G1 arrest is maintained in a lesion-independent manner. Sustained CHK2 activity is achieved through auto-activation and its acute inhibition enables cells to abrogate the G1-checkpoint and enter into S-phase. Accordingly, we show that CHK2 activity is lost in cells that recover from the G1 arrest, pointing to the involvement of a phosphatase with fast turnover. CONCLUSION: Our data indicate that G1 checkpoint maintenance relies on CHK2 and that its negative regulation is crucial for G1 checkpoint recovery after DSB induction.This research was funded by grants from MCIU/AEI/FEDER, UE (SAF2015-67562-R and RTI2018-097497-B-100) and Basque Government, Department of Education (IT1257-19) to A.M.Z., and Cancer Genomics Center Gravity Program (CGC.nl), Oncode Institute, Dutch Cancer Society (NKI 2014-6787) grants to R.H.M. I.G.-S. was supported with a postdoctoral fellowship from the Basque Country Government (Spain). J.V.-R. was supported by a postdoctoral fellowship from the University of the Basque Country (UPV/EHU).BMC202120212021info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10810/50544reponame:Addi. Archivo Digital para la Docencia y la Investigacióninstname:Universidad del País VascoInglésinfo:eu-repo/grantAgreement/MICINN/SAF2015-67562-R/info:eu-repo/grantAgreement/MICINN/RTI2018-097497-B-100/https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-021-00965-x#Ack1info:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by/3.0/es/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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Atribución 3.0 Españaoai:addi.ehu.eus:10810/505442026-06-18T09:23:17Z
dc.title.none.fl_str_mv Sustained CHK2 activity, but not ATM activity, is critical to maintain a G1 arrest after DNA damage in untransformed cells
title Sustained CHK2 activity, but not ATM activity, is critical to maintain a G1 arrest after DNA damage in untransformed cells
spellingShingle Sustained CHK2 activity, but not ATM activity, is critical to maintain a G1 arrest after DNA damage in untransformed cells
García Santisteban, Iraia
ATM
CHK2
DNA damage
G1 checkpoint
title_short Sustained CHK2 activity, but not ATM activity, is critical to maintain a G1 arrest after DNA damage in untransformed cells
title_full Sustained CHK2 activity, but not ATM activity, is critical to maintain a G1 arrest after DNA damage in untransformed cells
title_fullStr Sustained CHK2 activity, but not ATM activity, is critical to maintain a G1 arrest after DNA damage in untransformed cells
title_full_unstemmed Sustained CHK2 activity, but not ATM activity, is critical to maintain a G1 arrest after DNA damage in untransformed cells
title_sort Sustained CHK2 activity, but not ATM activity, is critical to maintain a G1 arrest after DNA damage in untransformed cells
dc.creator.none.fl_str_mv García Santisteban, Iraia
Llopis, Alba
Krenning, Lenno
Vallejo Rodríguez, Jon
Van den Broek, Bram
Zubiaga Elordieta, Ana María
Medem, René H.
author García Santisteban, Iraia
author_facet García Santisteban, Iraia
Llopis, Alba
Krenning, Lenno
Vallejo Rodríguez, Jon
Van den Broek, Bram
Zubiaga Elordieta, Ana María
Medem, René H.
author_role author
author2 Llopis, Alba
Krenning, Lenno
Vallejo Rodríguez, Jon
Van den Broek, Bram
Zubiaga Elordieta, Ana María
Medem, René H.
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv ATM
CHK2
DNA damage
G1 checkpoint
topic ATM
CHK2
DNA damage
G1 checkpoint
description BACKGROUND: The G1 checkpoint is a critical regulator of genomic stability in untransformed cells, preventing cell cycle progression after DNA damage. DNA double-strand breaks (DSBs) recruit and activate ATM, a kinase which in turn activates the CHK2 kinase to establish G1 arrest. While the onset of G1 arrest is well understood, the specific role that ATM and CHK2 play in regulating G1 checkpoint maintenance remains poorly characterized. RESULTS: Here we examine the impact of ATM and CHK2 activities on G1 checkpoint maintenance in untransformed cells after DNA damage caused by DSBs. We show that ATM becomes dispensable for G1 checkpoint maintenance as early as 1h after DSB induction. In contrast, CHK2 kinase activity is necessary to maintain the G1 arrest, independently of ATM, ATR, and DNA-PKcs, implying that the G1 arrest is maintained in a lesion-independent manner. Sustained CHK2 activity is achieved through auto-activation and its acute inhibition enables cells to abrogate the G1-checkpoint and enter into S-phase. Accordingly, we show that CHK2 activity is lost in cells that recover from the G1 arrest, pointing to the involvement of a phosphatase with fast turnover. CONCLUSION: Our data indicate that G1 checkpoint maintenance relies on CHK2 and that its negative regulation is crucial for G1 checkpoint recovery after DSB induction.
publishDate 2021
dc.date.none.fl_str_mv 2021
2021
2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/10810/50544
url http://hdl.handle.net/10810/50544
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv info:eu-repo/grantAgreement/MICINN/SAF2015-67562-R/
info:eu-repo/grantAgreement/MICINN/RTI2018-097497-B-100/
https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-021-00965-x#Ack1
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
http://creativecommons.org/licenses/by/3.0/es/
Atribución 3.0 España
eu_rights_str_mv openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/3.0/es/
Atribución 3.0 España
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv BMC
publisher.none.fl_str_mv BMC
dc.source.none.fl_str_mv reponame:Addi. Archivo Digital para la Docencia y la Investigación
instname:Universidad del País Vasco
instname_str Universidad del País Vasco
reponame_str Addi. Archivo Digital para la Docencia y la Investigación
collection Addi. Archivo Digital para la Docencia y la Investigación
repository.name.fl_str_mv
repository.mail.fl_str_mv
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