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Regulation of DNA damage response by trimeric G-proteins.
Abd El-Hafeez, Amer Ali; Sun, Nina; Chakraborty, Anirban; Ear, Jason; Roy, Suchismita; Chamarthi, Pranavi; Rajapakse, Navin; Das, Soumita; Luker, Kathryn E; Hazra, Tapas K; Luker, Gary D; Ghosh, Pradipta.
Afiliación
  • Abd El-Hafeez AA; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, USA.
  • Sun N; Pharmacology and Experimental Oncology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt.
  • Chakraborty A; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, USA.
  • Ear J; Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA.
  • Roy S; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, USA.
  • Chamarthi P; Biological Sciences Department, California State Polytechnic University, Pomona, CA 91768, USA.
  • Rajapakse N; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, USA.
  • Das S; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, USA.
  • Luker KE; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093, USA.
  • Hazra TK; Department of Pathology, University of California San Diego, La Jolla, CA 92093, USA.
  • Luker GD; Center for Molecular Imaging, Department of Radiology, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA.
  • Ghosh P; Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA.
iScience ; 26(2): 105973, 2023 Feb 17.
Article en En | MEDLINE | ID: mdl-36756378
Upon sensing DNA double-strand breaks (DSBs), eukaryotic cells either die or repair DSBs via one of the two competing pathways, i.e., non-homologous end-joining (NHEJ) or homologous recombination (HR). We show that cell fate after DSBs hinges on GIV/Girdin, a guanine nucleotide-exchange modulator of heterotrimeric Giα•ßγ protein. GIV suppresses HR by binding and sequestering BRCA1, a key coordinator of multiple steps within the HR pathway, away from DSBs; it does so using a C-terminal motif that binds BRCA1's BRCT-modules via both phospho-dependent and -independent mechanisms. Using another non-overlapping C-terminal motif GIV binds and activates Gi and enhances the "free" Gßγ→PI-3-kinase→Akt pathway, which promotes survival and is known to suppress HR, favor NHEJ. Absence of GIV, or loss of either of its C-terminal motifs enhanced cell death upon genotoxic stress. Because GIV selectively binds other BRCT-containing proteins suggests that G-proteins may fine-tune sensing, repair, and survival after diverse types of DNA damage.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: IScience Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: IScience Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos