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ATM-dependent phosphorylation of MRE11 controls extent of resection during homology directed repair by signalling through Exonuclease 1.
Kijas, Amanda W; Lim, Yi Chieh; Bolderson, Emma; Cerosaletti, Karen; Gatei, Magtouf; Jakob, Burkhard; Tobias, Frank; Taucher-Scholz, Gisela; Gueven, Nuri; Oakley, Greg; Concannon, Patrick; Wolvetang, Ernst; Khanna, Kum Kum; Wiesmüller, Lisa; Lavin, Martin F.
Afiliación
  • Kijas AW; The University of Queensland, UQ Centre for Clinical Research, University of Queensland, Brisbane, Queensland 4029, Australia.
  • Lim YC; Brain Cancer Research Unit, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia.
  • Bolderson E; Genome Stability Laboratory, Translational Research Institute, Queensland University of Technology, Queensland 4102, Australia.
  • Cerosaletti K; Translational Research Program, Benaroya Research Institute, Seattle, WA 981010, USA.
  • Gatei M; The University of Queensland, UQ Centre for Clinical Research, University of Queensland, Brisbane, Queensland 4029, Australia.
  • Jakob B; GSI Helmholtzzentrum für Schwerionenforschung, Darmstadt 64291, Germany.
  • Tobias F; GSI Helmholtzzentrum für Schwerionenforschung, Darmstadt 64291, Germany.
  • Taucher-Scholz G; GSI Helmholtzzentrum für Schwerionenforschung, Darmstadt 64291, Germany.
  • Gueven N; School of Medicine, Faculty of Health, University of Tasmania, Hobart, Tasmania 7001, Australia.
  • Oakley G; University of Nebraska College of Dentistry, Lincoln, NE 68583-0740, USA.
  • Concannon P; Genetics Institute, University of Florida, Gainesville, Florida, FL 3261, USA.
  • Wolvetang E; Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane 4072, Australia.
  • Khanna KK; Signal transduction, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia.
  • Wiesmüller L; Department of Obstetrics and Gynaecology, University of Ulm, Ulm 89075, Germany.
  • Lavin MF; The University of Queensland, UQ Centre for Clinical Research, University of Queensland, Brisbane, Queensland 4029, Australia m.lavin@uq.edu.au.
Nucleic Acids Res ; 43(17): 8352-67, 2015 Sep 30.
Article en En | MEDLINE | ID: mdl-26240375
The MRE11/RAD50/NBS1 (MRN) complex plays a central role as a sensor of DNA double strand breaks (DSB) and is responsible for the efficient activation of ataxia-telangiectasia mutated (ATM) kinase. Once activated ATM in turn phosphorylates RAD50 and NBS1, important for cell cycle control, DNA repair and cell survival. We report here that MRE11 is also phosphorylated by ATM at S676 and S678 in response to agents that induce DNA DSB, is dependent on the presence of NBS1, and does not affect the association of members of the complex or ATM activation. A phosphosite mutant (MRE11S676AS678A) cell line showed decreased cell survival and increased chromosomal aberrations after radiation exposure indicating a defect in DNA repair. Use of GFP-based DNA repair reporter substrates in MRE11S676AS678A cells revealed a defect in homology directed repair (HDR) but single strand annealing was not affected. More detailed investigation revealed that MRE11S676AS678A cells resected DNA ends to a greater extent at sites undergoing HDR. Furthermore, while ATM-dependent phosphorylation of Kap1 and SMC1 was normal in MRE11S676AS678A cells, there was no phosphorylation of Exonuclease 1 consistent with the defect in HDR. These results describe a novel role for ATM-dependent phosphorylation of MRE11 in limiting the extent of resection mediated through Exonuclease 1.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / Proteínas de Unión al ADN / Exodesoxirribonucleasas / Reparación del ADN por Recombinación / Proteínas de la Ataxia Telangiectasia Mutada Límite: Humans Idioma: En Revista: Nucleic Acids Res Año: 2015 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / Proteínas de Unión al ADN / Exodesoxirribonucleasas / Reparación del ADN por Recombinación / Proteínas de la Ataxia Telangiectasia Mutada Límite: Humans Idioma: En Revista: Nucleic Acids Res Año: 2015 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Reino Unido