Sustained CHK2 activity, but not ATM activity, is critical to maintain a G1 arrest after DNA damage in untransformed cells
dc.contributor.author | García Santisteban, Iraia | |
dc.contributor.author | Llopis, Alba | |
dc.contributor.author | Krenning, Lenno | |
dc.contributor.author | Vallejo Rodríguez, Jon | |
dc.contributor.author | Van den Broek, Bram | |
dc.contributor.author | Zubiaga Elordieta, Ana María | |
dc.contributor.author | Medem, René H. | |
dc.date.accessioned | 2021-03-10T13:36:02Z | |
dc.date.available | 2021-03-10T13:36:02Z | |
dc.date.issued | 2021-02-19 | |
dc.identifier.citation | BCM Biology 19(1) : (2021) // Article ID 35 | es_ES |
dc.identifier.issn | 1741-7007 | |
dc.identifier.uri | http://hdl.handle.net/10810/50544 | |
dc.description.abstract | 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. | es_ES |
dc.description.sponsorship | 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). | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | BMC | es_ES |
dc.relation | info:eu-repo/grantAgreement/MICINN/SAF2015-67562-R | es_ES |
dc.relation | info:eu-repo/grantAgreement/MICINN/RTI2018-097497-B-100 | es_ES |
dc.rights | info:eu-repo/semantics/openAccess | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by/3.0/es/ | * |
dc.subject | ATM | es_ES |
dc.subject | CHK2 | es_ES |
dc.subject | DNA damage | es_ES |
dc.subject | G1 checkpoint | es_ES |
dc.title | Sustained CHK2 activity, but not ATM activity, is critical to maintain a G1 arrest after DNA damage in untransformed cells | es_ES |
dc.type | info:eu-repo/semantics/article | es_ES |
dc.rights.holder | 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. | es_ES |
dc.rights.holder | Atribución 3.0 España | * |
dc.relation.publisherversion | https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-021-00965-x#Ack1 | es_ES |
dc.identifier.doi | 10.1186/s12915-021-00965-x | |
dc.departamentoes | Genética, antropología física y fisiología animal | es_ES |
dc.departamentoeu | Genetika,antropologia fisikoa eta animalien fisiologia | es_ES |
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