{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T14:52:38Z","timestamp":1777301558094,"version":"3.51.4"},"reference-count":64,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2023,5,14]],"date-time":"2023-05-14T00:00:00Z","timestamp":1684022400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002347","name":"Federal Ministry of Education and Research","doi-asserted-by":"publisher","award":["BMBF-02NUK037B"],"award-info":[{"award-number":["BMBF-02NUK037B"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002347","name":"Federal Ministry of Education and Research","doi-asserted-by":"publisher","award":["BMBF-02NUK043B"],"award-info":[{"award-number":["BMBF-02NUK043B"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002347","name":"Federal Ministry of Education and Research","doi-asserted-by":"publisher","award":["BMBF-02NUK054B"],"award-info":[{"award-number":["BMBF-02NUK054B"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002347","name":"Federal Ministry of Education and Research","doi-asserted-by":"publisher","award":["IL51.10"],"award-info":[{"award-number":["IL51.10"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002347","name":"Federal Ministry of Education and Research","doi-asserted-by":"publisher","award":["IL51.11"],"award-info":[{"award-number":["IL51.11"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002347","name":"Federal Ministry of Education and Research","doi-asserted-by":"publisher","award":["GRK1739"],"award-info":[{"award-number":["GRK1739"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002347","name":"Federal Ministry of Education and Research","doi-asserted-by":"publisher","award":["50WB1836"],"award-info":[{"award-number":["50WB1836"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002347","name":"Federal Ministry of Education and Research","doi-asserted-by":"publisher","award":["57515880"],"award-info":[{"award-number":["57515880"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["BMBF-02NUK037B"],"award-info":[{"award-number":["BMBF-02NUK037B"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["BMBF-02NUK043B"],"award-info":[{"award-number":["BMBF-02NUK043B"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["BMBF-02NUK054B"],"award-info":[{"award-number":["BMBF-02NUK054B"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["IL51.10"],"award-info":[{"award-number":["IL51.10"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["IL51.11"],"award-info":[{"award-number":["IL51.11"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["GRK1739"],"award-info":[{"award-number":["GRK1739"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["50WB1836"],"award-info":[{"award-number":["50WB1836"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"publisher","award":["57515880"],"award-info":[{"award-number":["57515880"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006360","name":"German Federal Ministry for Economic Affairs","doi-asserted-by":"publisher","award":["BMBF-02NUK037B"],"award-info":[{"award-number":["BMBF-02NUK037B"]}],"id":[{"id":"10.13039\/501100006360","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006360","name":"German Federal Ministry for Economic Affairs","doi-asserted-by":"publisher","award":["BMBF-02NUK043B"],"award-info":[{"award-number":["BMBF-02NUK043B"]}],"id":[{"id":"10.13039\/501100006360","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006360","name":"German Federal Ministry for Economic Affairs","doi-asserted-by":"publisher","award":["BMBF-02NUK054B"],"award-info":[{"award-number":["BMBF-02NUK054B"]}],"id":[{"id":"10.13039\/501100006360","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006360","name":"German Federal Ministry for Economic Affairs","doi-asserted-by":"publisher","award":["IL51.10"],"award-info":[{"award-number":["IL51.10"]}],"id":[{"id":"10.13039\/501100006360","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006360","name":"German Federal Ministry for Economic Affairs","doi-asserted-by":"publisher","award":["IL51.11"],"award-info":[{"award-number":["IL51.11"]}],"id":[{"id":"10.13039\/501100006360","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006360","name":"German Federal Ministry for Economic Affairs","doi-asserted-by":"publisher","award":["GRK1739"],"award-info":[{"award-number":["GRK1739"]}],"id":[{"id":"10.13039\/501100006360","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006360","name":"German Federal Ministry for Economic Affairs","doi-asserted-by":"publisher","award":["50WB1836"],"award-info":[{"award-number":["50WB1836"]}],"id":[{"id":"10.13039\/501100006360","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006360","name":"German Federal Ministry for Economic Affairs","doi-asserted-by":"publisher","award":["57515880"],"award-info":[{"award-number":["57515880"]}],"id":[{"id":"10.13039\/501100006360","id-type":"DOI","asserted-by":"publisher"}]},{"name":"DAAD Project","award":["BMBF-02NUK037B"],"award-info":[{"award-number":["BMBF-02NUK037B"]}]},{"name":"DAAD Project","award":["BMBF-02NUK043B"],"award-info":[{"award-number":["BMBF-02NUK043B"]}]},{"name":"DAAD Project","award":["BMBF-02NUK054B"],"award-info":[{"award-number":["BMBF-02NUK054B"]}]},{"name":"DAAD Project","award":["IL51.10"],"award-info":[{"award-number":["IL51.10"]}]},{"name":"DAAD Project","award":["IL51.11"],"award-info":[{"award-number":["IL51.11"]}]},{"name":"DAAD Project","award":["GRK1739"],"award-info":[{"award-number":["GRK1739"]}]},{"name":"DAAD Project","award":["50WB1836"],"award-info":[{"award-number":["50WB1836"]}]},{"name":"DAAD Project","award":["57515880"],"award-info":[{"award-number":["57515880"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>We have recently reported that in G2-phase cells (but not S-phase cells) sustaining low loads of DNA double-strand break (DSBs), ATM and ATR regulate the G2-checkpoint epistatically, with ATR at the output-node, interfacing with the cell cycle through Chk1. However, although inhibition of ATR nearly completely abrogated the checkpoint, inhibition of Chk1 using UCN-01 generated only partial responses. This suggested that additional kinases downstream of ATR were involved in the transmission of the signal to the cell cycle engine. Additionally, the broad spectrum of kinases inhibited by UCN-01 pointed to uncertainties in the interpretation that warranted further investigations. Here, we show that more specific Chk1 inhibitors exert an even weaker effect on G2-checkpoint, as compared to ATR inhibitors and UCN-01, and identify the MAPK p38\u03b1 and its downstream target MK2 as checkpoint effectors operating as backup to Chk1. These observations further expand the spectrum of p38\/MK2 signaling to G2-checkpoint activation, extend similar studies in cells exposed to other DNA damaging agents and consolidate a role of p38\/MK2 as a backup kinase module, adding to similar backup functions exerted in p53 deficient cells. The results extend the spectrum of actionable strategies and targets in current efforts to enhance the radiosensitivity in tumor cells.<\/jats:p>","DOI":"10.3390\/cells12101387","type":"journal-article","created":{"date-parts":[[2023,5,15]],"date-time":"2023-05-15T08:28:16Z","timestamp":1684139296000},"page":"1387","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The p38\/MK2 Pathway Functions as Chk1-Backup Downstream of ATM\/ATR in G2-Checkpoint Activation in Cells Exposed to Ionizing Radiation"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-7126-316X","authenticated-orcid":false,"given":"Daxian","family":"Luo","sequence":"first","affiliation":[{"name":"Institute of Medical Radiation Biology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"},{"name":"Division of Experimental Radiation Biology, Department of Radiation Therapy, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emil","family":"Mladenov","sequence":"additional","affiliation":[{"name":"Institute of Medical Radiation Biology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"},{"name":"Division of Experimental Radiation Biology, Department of Radiation Therapy, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9696-1006","authenticated-orcid":false,"given":"Aashish","family":"Soni","sequence":"additional","affiliation":[{"name":"Institute of Medical Radiation Biology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"},{"name":"Division of Experimental Radiation Biology, Department of Radiation Therapy, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin","family":"Stuschke","sequence":"additional","affiliation":[{"name":"Division of Experimental Radiation Biology, Department of Radiation Therapy, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"},{"name":"German Cancer Consortium (DKTK), Partner Site University Hospital Essen, 45147 Essen, Germany"},{"name":"German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1152-5342","authenticated-orcid":false,"given":"George","family":"Iliakis","sequence":"additional","affiliation":[{"name":"Institute of Medical Radiation Biology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"},{"name":"Division of Experimental Radiation Biology, Department of Radiation Therapy, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1071","DOI":"10.1038\/nature08467","article-title":"The DNA-damage response in human biology and disease","volume":"461","author":"Jackson","year":"2009","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.molcel.2010.09.019","article-title":"The DNA Damage Response: Making It Safe to Play with Knives","volume":"40","author":"Ciccia","year":"2010","journal-title":"Mol. Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/j.cell.2013.01.007","article-title":"Mechanisms of Programmed DNA Lesions and Genomic Instability in the Immune System","volume":"152","author":"Alt","year":"2013","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1016\/j.molcel.2017.05.015","article-title":"ATM, ATR, and DNA-PK: The Trinity at the Heart of the DNA Damage Response","volume":"66","author":"Blackford","year":"2017","journal-title":"Mol. Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/nrm3546","article-title":"The ATM protein kinase: Regulating the cellular response to genotoxic stress, and more","volume":"14","author":"Shiloh","year":"2013","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5834","DOI":"10.1038\/sj.onc.1206682","article-title":"DNA Damage Checkpoint Control in Cells Exposed to Ionizing Radiation","volume":"22","author":"Iliakis","year":"2003","journal-title":"Oncogene"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1495","DOI":"10.1126\/science.277.5331.1495","article-title":"Cdc25 Mitotic Inducer Targeted by Chk1 DNA Damage Checkpoint Kinase","volume":"277","author":"Furnari","year":"1997","journal-title":"Science"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"28580","DOI":"10.1074\/jbc.M304027200","article-title":"14-3-3 Acts as an Intramolecular Bridge to Regulate cdc25B Localization and Activity","volume":"278","author":"Giles","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1101\/gad.13.9.1067","article-title":"Binding of 14-3-3 proteins and nuclear export control the intracellular localization of the mitotic inducer Cdc25","volume":"13","author":"Kumagai","year":"1999","journal-title":"Genes Dev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1126\/science.277.5331.1501","article-title":"Mitotic and G2 Checkpoint Control: Regulation of 14-3-3 Protein Binding by Phosphorylation of Cdc25c on Serine-216","volume":"277","author":"Peng","year":"1997","journal-title":"Science"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5911","DOI":"10.1093\/emboj\/cdf567","article-title":"Regulation of G2\/M Events by Cdc25a through Phosphorylation-Dependent Modulation of Its Stability","volume":"21","author":"Mailand","year":"2002","journal-title":"EMBO J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3853","DOI":"10.1128\/MCB.21.12.3853-3861.2001","article-title":"Absence of Apparent Phenotype in Mice Lacking Cdc25C Protein Phosphatase","volume":"21","author":"Chen","year":"2001","journal-title":"Mol. Cell. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"14597","DOI":"10.1038\/s41598-019-51071-6","article-title":"DNA-Pkcs and Atm Epistatically Suppress DNA End Resection and Hyperactivation of Atr-Dependent G2-Checkpoint in S-Phase Irradiated Cells","volume":"9","author":"Mladenov","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"8255","DOI":"10.1038\/s41598-019-44771-6","article-title":"Radiation-dose-dependent functional synergisms between ATM, ATR and DNA-PKcs in checkpoint control and resection in G2-phase","volume":"9","author":"Mladenov","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Xiao, H., Li, F., Mladenov, E., Soni, A., Mladenova, V., Pan, B., Dueva, R., Stuschke, M., Timmermann, B., and Iliakis, G. (2022). Increased Resection at DSBs in G2-Phase Is a Unique Phenotype Associated with DNA-PKcs Defects That Is Not Shared by Other Factors of c-NHEJ. Cells, 11.","DOI":"10.3390\/cells11132099"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1905","DOI":"10.1093\/nar\/gkz1167","article-title":"Strong Suppression of Gene Conversion with Increasing DNA Double-Strand Break Load Delimited by 53bp1 and Rad52","volume":"48","author":"Mladenov","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.molcel.2004.11.021","article-title":"Mapkap Kinase-2 Is a Cell Cycle Checkpoint Kinase That Regulates the G2\/M Transition and S Phase Progression in Response to Uv Irradiation","volume":"17","author":"Manke","year":"2005","journal-title":"Mol. Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.ccr.2006.11.024","article-title":"p53-Deficient Cells Rely on ATM- and ATR-Mediated Checkpoint Signaling through the p38MAPK\/MK2 Pathway for Survival after DNA Damage","volume":"11","author":"Reinhardt","year":"2007","journal-title":"Cancer Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.molcel.2010.09.018","article-title":"DNA Damage Activates a Spatially Distinct Late Cytoplasmic Cell-Cycle Checkpoint Network Controlled by Mk2-Mediated Rna Stabilization","volume":"40","author":"Reinhardt","year":"2010","journal-title":"Mol. Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1038\/35075107","article-title":"Initiation of a G2\/M Checkpoint after Ultraviolet Radiation Requires P38 Kinase","volume":"411","author":"Bulavin","year":"2001","journal-title":"Nature"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"8306","DOI":"10.1128\/MCB.23.22.8306-8315.2003","article-title":"The p38 Mitogen-Activated Protein Kinase Pathway Links the DNA Mismatch Repair System to the G2 Checkpoint and to Resistance to Chemotherapeutic DNA-Methylating Agents","volume":"23","author":"Hirose","year":"2003","journal-title":"Mol. Cell. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.3171\/jns.2004.100.6.1060","article-title":"Cooperative function of Chk1 and p38 pathways in activating G2 arrest following exposure to temozolomide","volume":"100","author":"Hirose","year":"2004","journal-title":"J. Neurosurg."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1083\/jcb.200306006","article-title":"DNA damage-induced replication arrest in Xenopus egg extracts","volume":"163","author":"Stokes","year":"2003","journal-title":"J. Cell Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1083\/jcb.200405167","article-title":"Topoisomerase Ii and Histone Deacetylase Inhibitors Delay the G2\/M Transition by Triggering the P38 Mapk Checkpoint Pathway","volume":"166","author":"Mikhailov","year":"2004","journal-title":"J. Cell Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"27213","DOI":"10.1074\/jbc.270.45.27213","article-title":"Constitutive Activation of Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 by Mutation of Phosphorylation Sites and an a-Helix Motif (*)","volume":"270","author":"Engel","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.cell.2015.05.053","article-title":"A Synergistic Interaction between Chk1- and Mk2 Inhibitors in Kras-Mutant Cancer","volume":"162","author":"Dietlein","year":"2015","journal-title":"Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1038\/s41580-020-00322-w","article-title":"Diversity and versatility of p38 kinase signalling in health and disease","volume":"22","author":"Canovas","year":"2021","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Han, J., Wu, J., and Silke, J. (2020). An Overview of Mammalian P38 Mitogen-Activated Protein Kinases, Central Regulators of Cell Stress and Receptor Signaling [Version 1; Peer Review: 2 Approved]. F1000Research, 9.","DOI":"10.12688\/f1000research.22092.1"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1177\/1947601913485414","article-title":"Mitogen-Activated Protein Kinases and Their Role in Radiation Response","volume":"4","author":"Munshi","year":"2013","journal-title":"Genes Cancer"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1016\/j.bbadis.2009.12.009","article-title":"Pathological roles of MAPK signaling pathways in human diseases","volume":"1802","author":"Kim","year":"2010","journal-title":"Biochim. Biophys. Acta (BBA)\u2014Mol. Basis Dis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1016\/S0163-7258(99)00008-X","article-title":"p38 Mitogen-Activated Protein Kinase Inhibitors\u2014Mechanisms and Therapeutic Potentials","volume":"82","author":"Lee","year":"1999","journal-title":"Pharmacol. Ther."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"14951","DOI":"10.1002\/jcp.28334","article-title":"Ras\/Mapk Signaling Functions in Oxidative Stress, DNA Damage Response and Cancer Progression","volume":"234","author":"Rezatabar","year":"2019","journal-title":"J. Cell Physiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1007\/s11010-008-9987-y","article-title":"Differential Activation of Mitogen-Activated Protein Kinases Following High and Low Let Radiation in Murine Macrophage Cell Line","volume":"324","author":"Narang","year":"2009","journal-title":"Mol. Cell Biochem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5885","DOI":"10.1038\/sj.onc.1206701","article-title":"MAPK pathways in radiation responses","volume":"22","author":"Dent","year":"2003","journal-title":"Oncogene"},{"key":"ref_35","first-page":"237","article-title":"Protein Kinase Cdelta Overexpression Enhances Radiation Sensitivity Via Extracellular Regulated Protein Kinase 1\/2 Activation, Abolishing the Radiation-Induced G(2)-M Arrest","volume":"13","author":"Lee","year":"2002","journal-title":"Cell Growth Differ."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1562\/0031-8655(2000)071<0455:ROTPAM>2.0.CO;2","article-title":"Role of the P38 and Mek-1\/2\/P42\/44 Map Kinase Pathways in the Differential Activation of Human Immunodeficiency Virus Gene Expression by Ultraviolet and Ionizing Radiation","volume":"71","author":"Taher","year":"2000","journal-title":"Photochem. Photobiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1667\/0033-7587(2000)153[0245:STACRR]2.0.CO;2","article-title":"Signal Transduction and Cellular Radiation Responses","volume":"153","author":"Dent","year":"2000","journal-title":"Radiat. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/S0959-437X(01)00270-2","article-title":"P38 and Chk1 Kinases: Different Conductors for the G2\/M Checkpoint Symphony","volume":"12","author":"Bulavin","year":"2002","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4543","DOI":"10.1128\/MCB.20.13.4543-4552.2000","article-title":"Involvement of the Mkk6-P38\u03b3 Cascade in \u0393-Radiation-Induced Cell Cycle Arrest","volume":"20","author":"Wang","year":"2000","journal-title":"Mol. Cell Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1128\/MCB.22.4.1049-1059.2002","article-title":"Two Molecularly Distinct G2\/M Checkpoints Are Induced by Ionizing Irradiation","volume":"22","author":"Xu","year":"2002","journal-title":"Mol. Cell Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1093\/emboj\/17.1.159","article-title":"Overexpression of a kinase-inactive ATR protein causes sensitivity to DNA-damaging agents and defects in cell cycle checkpoints","volume":"17","author":"Cliby","year":"1998","journal-title":"EMBO J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"9346","DOI":"10.1074\/jbc.M513265200","article-title":"Rapid Activation of ATR by Ionizing Radiation Requires ATM and Mre11","volume":"281","author":"Myers","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1038\/embor.2009.60","article-title":"Distinct roles of ATR and DNA-PKcs in triggering DNA damage responses in ATM-deficient cells","volume":"10","author":"Tomimatsu","year":"2009","journal-title":"EMBO Rep."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3371","DOI":"10.1128\/MCB.01644-09","article-title":"Role of Atm and the Damage Response Mediator Proteins 53bp1 and Mdc1 in the Maintenance of G2\/M Checkpoint Arrest","volume":"30","author":"Shibata","year":"2010","journal-title":"Mol. Cell Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.dnarep.2014.11.004","article-title":"The Complexity of DNA Double Strand Break Is a Crucial Factor for Activating Atr Signaling Pathway for G2\/M Checkpoint Regulation Regardless of Atm Function","volume":"25","author":"Xue","year":"2015","journal-title":"DNA Repair"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Mladenova, V., Mladenov, E., Scholz, M., Stuschke, M., and Iliakis, G. (2021). Strong Shift to ATR-Dependent Regulation of the G2-Checkpoint after Exposure to High-LET Radiation. Life, 11.","DOI":"10.3390\/life11060560"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"6521","DOI":"10.1128\/MCB.22.18.6521-6532.2002","article-title":"Chk2 Is a Tumor Suppressor That Regulates Apoptosis in both an Ataxia Telangiectasia Mutated (ATM)-Dependent and an ATM-Independent Manner","volume":"22","author":"Hirao","year":"2002","journal-title":"Mol. Cell Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1893","DOI":"10.1126\/science.282.5395.1893","article-title":"Linkage of ATM to Cell Cycle Regulation by the Chk2 Protein Kinase","volume":"282","author":"Matsuoka","year":"1998","journal-title":"Science"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1038\/sj.onc.1210702","article-title":"Chk2 Is Required for Optimal Mitotic Delay in Response to Irradiation-Induced DNA Damage Incurred in G2 Phase","volume":"27","author":"Rainey","year":"2008","journal-title":"Oncogene"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1084\/jem.20051923","article-title":"ATM regulates ATR chromatin loading in response to DNA double-strand breaks","volume":"203","author":"Cuadrado","year":"2006","journal-title":"J. Exp. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1126\/science.1065521","article-title":"ATR and ATRIP: Partners in Checkpoint Signaling","volume":"294","author":"Cortez","year":"2001","journal-title":"Science"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2320","DOI":"10.1021\/jm101488z","article-title":"Discovery of Potent and Selective Inhibitors of Ataxia Telangiectasia Mutated and Rad3 Related (ATR) Protein Kinase as Potential Anticancer Agents","volume":"54","author":"Charrier","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.ctrv.2013.03.002","article-title":"Targeting Atr in DNA Damage Response and Cancer Therapeutics","volume":"40","author":"Fokas","year":"2014","journal-title":"Cancer Treat. Rev."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"4780","DOI":"10.1158\/1078-0432.CCR-15-0479","article-title":"Molecular Pathways: Targeting ATR in Cancer Therapy","volume":"21","author":"Karnitz","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2394","DOI":"10.1158\/1535-7163.MCT-07-2391","article-title":"Breaching the DNA Damage Checkpoint Via Pf-00477736, a Novel Small-Molecule Inhibitor of Checkpoint Kinase 1","volume":"7","author":"Blasina","year":"2008","journal-title":"Mol. Cancer Ther."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Gurgis, F., Ziaziaris, W., and Munoz, L. (2013). Mapk-Activated Protein Kinase 2 (Mk2) in Neuroinflammation, Hsp27 Phosphorylation and Cell Cycle: Role and Targeting. Mol. Pharmacol.","DOI":"10.1124\/mol.113.090365"},{"key":"ref_57","first-page":"eabb5445","article-title":"The Mk2\/Hsp27 Axis Is a Major Survival Mechanism for Pancreatic Ductal Adenocarcinoma under Genotoxic Stress","volume":"13","author":"Grierson","year":"2021","journal-title":"Sci. Transl. Med."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1016\/S0021-9258(18)48354-8","article-title":"Human HSP27 is phosphorylated at serines 78 and 82 by heat shock and mitogen-activated kinases that recognize the same amino acid motif as S6 kinase II","volume":"267","author":"Landry","year":"1992","journal-title":"J. Biol. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Soni, A., Duan, X., Stuschke, M., and Iliakis, G. (2022). ATR Contributes More Than ATM in Intra-S-Phase Checkpoint Activation after IR, and DNA-PKcs Facilitates Recovery: Evidence for Modular Integration of ATM\/ATR\/DNA-PKcs Functions. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23147506"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1038\/10061","article-title":"Mapkap Kinase 2 Is Essential for Lps-Induced Tnf-Alpha Biosynthesis","volume":"1","author":"Kotlyarov","year":"1999","journal-title":"Nat. Cell Biol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1049","DOI":"10.1016\/S0960-9822(98)70442-7","article-title":"Nuclear export of the stress-activated protein kinase p38 mediated by its substrate MAPKAP kinase-2","volume":"8","author":"Hooper","year":"1998","journal-title":"Curr. Biol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"4827","DOI":"10.1128\/MCB.22.13.4827-4835.2002","article-title":"Distinct Cellular Functions of MK2","volume":"22","author":"Kotlyarov","year":"2002","journal-title":"Mol. Cell Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1935","DOI":"10.1158\/1535-7163.MCT-06-0077","article-title":"Differential Roles of Checkpoint Kinase 1, Checkpoint Kinase 2, and Mitogen-Activated Protein Kinase\u2013Activated Protein Kinase 2 in Mediating DNA Damage\u2013Induced Cell Cycle Arrest: Implications for Cancer Therapy","volume":"5","author":"Xiao","year":"2006","journal-title":"Mol. Cancer Ther."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1038\/sj.onc.1204177","article-title":"Cdc25-dependent activation of cyclin A\/cdk2 is blocked in G2 phase arrested cells independently of ATM\/ATR","volume":"20","author":"Goldstone","year":"2001","journal-title":"Oncogene"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/10\/1387\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:34:36Z","timestamp":1760124876000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/10\/1387"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,14]]},"references-count":64,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["cells12101387"],"URL":"https:\/\/doi.org\/10.3390\/cells12101387","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,14]]}}}