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Pyruvate kinase M2 regulates homologous recombination-mediated DNA double-strand break repair.
Sizemore, Steven T; Zhang, Manchao; Cho, Ju Hwan; Sizemore, Gina M; Hurwitz, Brian; Kaur, Balveen; Lehman, Norman L; Ostrowski, Michael C; Robe, Pierre A; Miao, Weili; Wang, Yinsheng; Chakravarti, Arnab; Xia, Fen.
Afiliación
  • Sizemore ST; Department of Radiation Oncology, Arthur G James Comprehensive Cancer Center and Richard L. Solove Research Institute, The Ohio State University Medical Center, Columbus, OH, 43210, USA.
  • Zhang M; Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.
  • Cho JH; Department of Radiation Oncology, Arthur G James Comprehensive Cancer Center and Richard L. Solove Research Institute, The Ohio State University Medical Center, Columbus, OH, 43210, USA.
  • Sizemore GM; Department of Cancer Biology & Genetics, Arthur G James Comprehensive Cancer Center and Richard L. Solove Research Institute, The Ohio State University Medical Center, Columbus, OH, 43210, USA.
  • Hurwitz B; Department of Neurological Surgery, Arthur G James Comprehensive Cancer Center and Richard L. Solove Research Institute, The Ohio State University Medical Center, Columbus, OH, 43210, USA.
  • Kaur B; Department of Radiation Oncology, Arthur G James Comprehensive Cancer Center and Richard L. Solove Research Institute, The Ohio State University Medical Center, Columbus, OH, 43210, USA.
  • Lehman NL; Department of Neurological Surgery, Arthur G James Comprehensive Cancer Center and Richard L. Solove Research Institute, The Ohio State University Medical Center, Columbus, OH, 43210, USA.
  • Ostrowski MC; Department of Pathology, Arthur G James Comprehensive Cancer Center and Richard L. Solove Research Institute, The Ohio State University Medical Center, Columbus, OH, 43210, USA.
  • Robe PA; Department of Cancer Biology & Genetics, Arthur G James Comprehensive Cancer Center and Richard L. Solove Research Institute, The Ohio State University Medical Center, Columbus, OH, 43210, USA.
  • Miao W; Department of Neurology and Neurosurgery, Rudolf Magnus Brain Institute, University Medical Center of Utrecht, Utrecht, The Netherlands.
  • Wang Y; Departments of Neurosurgery and Human Genetics, University of Liege, Liege, Belgium.
  • Chakravarti A; Department of Chemistry, University of California, Riverside, CA, 92521, USA.
  • Xia F; Department of Chemistry, University of California, Riverside, CA, 92521, USA.
Cell Res ; 28(11): 1090-1102, 2018 11.
Article en En | MEDLINE | ID: mdl-30297868
Resistance to genotoxic therapies is a primary cause of treatment failure and tumor recurrence. The underlying mechanisms that activate the DNA damage response (DDR) and allow cancer cells to escape the lethal effects of genotoxic therapies remain unclear. Here, we uncover an unexpected mechanism through which pyruvate kinase M2 (PKM2), the highly expressed PK isoform in cancer cells and a master regulator of cancer metabolic reprogramming, integrates with the DDR to directly promote DNA double-strand break (DSB) repair. In response to ionizing radiation and oxidative stress, ATM phosphorylates PKM2 at T328 resulting in its nuclear accumulation. pT328-PKM2 is required and sufficient to promote homologous recombination (HR)-mediated DNA DSB repair through phosphorylation of CtBP-interacting protein (CtIP) on T126 to increase CtIP's recruitment at DSBs and resection of DNA ends. Disruption of the ATM-PKM2-CtIP axis sensitizes cancer cells to a variety of DNA-damaging agents and PARP1 inhibition. Furthermore, increased nuclear pT328-PKM2 level is associated with significantly worse survival in glioblastoma patients. Combined, these data advocate the use of PKM2-targeting strategies as a means to not only disrupt cancer metabolism but also inhibit an important mechanism of resistance to genotoxic therapies.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Hormonas Tiroideas / Proteínas Portadoras / Reparación del ADN / Roturas del ADN de Doble Cadena / Proteínas de la Membrana Límite: Animals / Female / Humans Idioma: En Revista: Cell Res Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Hormonas Tiroideas / Proteínas Portadoras / Reparación del ADN / Roturas del ADN de Doble Cadena / Proteínas de la Membrana Límite: Animals / Female / Humans Idioma: En Revista: Cell Res Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido