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Article: A positive role for c-Abl in Atm and Atr activation in DNA damage response

TitleA positive role for c-Abl in Atm and Atr activation in DNA damage response
Authors
Issue Date2011
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/cdd
Citation
Cell Death And Differentiation, 2011, v. 18 n. 1, p. 5-15 How to Cite?
AbstractDNA damage triggers Atm- and/or Atr-dependent signaling pathways to control cell cycle progression, apoptosis, and DNA repair. However, how Atm and Atr are activated is not fully understood. One of the downstream targets of Atm is non-receptor tyrosine kinase c-Abl, which is phosphorylated and activated by Atm. The current view is that c-Abl relays pro-apoptotic signals from Atm to p73 and p53. Here we show that c-Abl deficiency resulted in a broad spectrum of defects in cell response to genotoxic stress, including activation of Chk1 and Chk2, activation of p53, nuclear foci formation, apoptosis, and DNA repair, suggesting that c-Abl might also act upstream of the DNA damage-activated signaling cascades in addition to its role in p73 and p53 regulation. Indeed, we found that c-Abl is required for proper activation of both Atm and Atr. c-Abl is bound to the chromatin and shows enhanced interaction with Atm and Atr in response to DNA damage. c-Abl can phosphorylate Atr on Y291 and Y310 and this phosphorylation appears to have a positive role in Atr activation under genotoxic stress. These findings suggest that Atm-mediated c-Abl activation in cell response to double-stranded DNA breaks might facilitate the activation of both Atm and Atr to regulate their downstream cellular events. © 2011 Macmillan Publishers Limited All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/183400
ISSN
2015 Impact Factor: 8.218
2015 SCImago Journal Rankings: 4.219
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorWang, Xen_US
dc.contributor.authorZeng, Len_US
dc.contributor.authorWang, Jen_US
dc.contributor.authorChau, JFLen_US
dc.contributor.authorLai, KPen_US
dc.contributor.authorJia, Den_US
dc.contributor.authorPoonepalli, Aen_US
dc.contributor.authorHande, MPen_US
dc.contributor.authorLiu, Hen_US
dc.contributor.authorHe, Gen_US
dc.contributor.authorHe, Len_US
dc.contributor.authorLi, Ben_US
dc.date.accessioned2013-05-27T07:12:37Z-
dc.date.available2013-05-27T07:12:37Z-
dc.date.issued2011en_US
dc.identifier.citationCell Death And Differentiation, 2011, v. 18 n. 1, p. 5-15en_US
dc.identifier.issn1350-9047en_US
dc.identifier.urihttp://hdl.handle.net/10722/183400-
dc.description.abstractDNA damage triggers Atm- and/or Atr-dependent signaling pathways to control cell cycle progression, apoptosis, and DNA repair. However, how Atm and Atr are activated is not fully understood. One of the downstream targets of Atm is non-receptor tyrosine kinase c-Abl, which is phosphorylated and activated by Atm. The current view is that c-Abl relays pro-apoptotic signals from Atm to p73 and p53. Here we show that c-Abl deficiency resulted in a broad spectrum of defects in cell response to genotoxic stress, including activation of Chk1 and Chk2, activation of p53, nuclear foci formation, apoptosis, and DNA repair, suggesting that c-Abl might also act upstream of the DNA damage-activated signaling cascades in addition to its role in p73 and p53 regulation. Indeed, we found that c-Abl is required for proper activation of both Atm and Atr. c-Abl is bound to the chromatin and shows enhanced interaction with Atm and Atr in response to DNA damage. c-Abl can phosphorylate Atr on Y291 and Y310 and this phosphorylation appears to have a positive role in Atr activation under genotoxic stress. These findings suggest that Atm-mediated c-Abl activation in cell response to double-stranded DNA breaks might facilitate the activation of both Atm and Atr to regulate their downstream cellular events. © 2011 Macmillan Publishers Limited All rights reserved.en_US
dc.languageengen_US
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/cdden_US
dc.relation.ispartofCell Death and Differentiationen_US
dc.subject.meshAnimalsen_US
dc.subject.meshAntibiotics, Antineoplastic - Pharmacologyen_US
dc.subject.meshApoptosisen_US
dc.subject.meshCell Cycle Proteins - Metabolismen_US
dc.subject.meshCell Lineen_US
dc.subject.meshDna Breaks, Double-Strandeden_US
dc.subject.meshDna Damageen_US
dc.subject.meshDna Repairen_US
dc.subject.meshDna-Binding Proteins - Metabolismen_US
dc.subject.meshDoxorubicin - Pharmacologyen_US
dc.subject.meshFibroblasts - Metabolismen_US
dc.subject.meshMiceen_US
dc.subject.meshMice, Knockouten_US
dc.subject.meshNuclear Proteins - Metabolismen_US
dc.subject.meshPhosphorylationen_US
dc.subject.meshProtein Kinases - Metabolismen_US
dc.subject.meshProtein-Serine-Threonine Kinases - Metabolismen_US
dc.subject.meshProto-Oncogene Proteins C-Abl - Genetics - Metabolism - Physiologyen_US
dc.subject.meshTumor Suppressor Protein P53 - Metabolismen_US
dc.subject.meshTumor Suppressor Proteins - Metabolismen_US
dc.titleA positive role for c-Abl in Atm and Atr activation in DNA damage responseen_US
dc.typeArticleen_US
dc.identifier.emailLai, KP: ballllai@hotmail.comen_US
dc.identifier.authorityLai, KP=rp01753en_US
dc.description.naturelink_to_OA_fulltexten_US
dc.identifier.doi10.1038/cdd.2010.106en_US
dc.identifier.pmid20798688-
dc.identifier.scopuseid_2-s2.0-78650087114en_US
dc.identifier.hkuros223777-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-78650087114&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume18en_US
dc.identifier.issue1en_US
dc.identifier.spage5en_US
dc.identifier.epage15en_US
dc.identifier.isiWOS:000285289900003-
dc.publisher.placeUnited Kingdomen_US
dc.identifier.scopusauthoridWang, X=7501852661en_US
dc.identifier.scopusauthoridZeng, L=7401904330en_US
dc.identifier.scopusauthoridWang, J=35725021000en_US
dc.identifier.scopusauthoridChau, JFL=15828893500en_US
dc.identifier.scopusauthoridLai, KP=7402135707en_US
dc.identifier.scopusauthoridJia, D=24484433400en_US
dc.identifier.scopusauthoridPoonepalli, A=12766784000en_US
dc.identifier.scopusauthoridHande, MP=7003377506en_US
dc.identifier.scopusauthoridLiu, H=36067405700en_US
dc.identifier.scopusauthoridHe, G=35313834400en_US
dc.identifier.scopusauthoridHe, L=55158160500en_US
dc.identifier.scopusauthoridLi, B=7410078924en_US

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