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TIRR inhibits the 53BP1-p53 complex to alter cell-fate programs.
Parnandi, Nishita; Rendo, Veronica; Cui, Gaofeng; Botuyan, Maria Victoria; Remisova, Michaela; Nguyen, Huy; Drané, Pascal; Beroukhim, Rameen; Altmeyer, Matthias; Mer, Georges; Chowdhury, Dipanjan.
Afiliación
  • Parnandi N; Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
  • Rendo V; Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; Cancer Program, Broad Institute, 415 Main Street, Cambridge, MA 02142, USA; Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA; Broad Institute of Harvard
  • Cui G; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.
  • Botuyan MV; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.
  • Remisova M; Department of Molecular Mechanisms of Disease, University of Zurich, Zurich, Switzerland.
  • Nguyen H; Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
  • Drané P; Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
  • Beroukhim R; Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; Cancer Program, Broad Institute, 415 Main Street, Cambridge, MA 02142, USA; Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA; Broad Institute of Harvard
  • Altmeyer M; Department of Molecular Mechanisms of Disease, University of Zurich, Zurich, Switzerland.
  • Mer G; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, USA.
  • Chowdhury D; Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: dipanjan_chowdhury@
Mol Cell ; 81(12): 2583-2595.e6, 2021 06 17.
Article en En | MEDLINE | ID: mdl-33961797
ABSTRACT
53BP1 influences genome stability via two independent mechanisms (1) regulating DNA double-strand break (DSB) repair and (2) enhancing p53 activity. We discovered a protein, Tudor-interacting repair regulator (TIRR), that associates with the 53BP1 Tudor domain and prevents its recruitment to DSBs. Here, we elucidate how TIRR affects 53BP1 function beyond its recruitment to DSBs and biochemically links the two distinct roles of 53BP1. Loss of TIRR causes an aberrant increase in the gene transactivation function of p53, affecting several p53-mediated cell-fate programs. TIRR inhibits the complex formation between the Tudor domain of 53BP1 and a dimethylated form of p53 (K382me2) that is poised for transcriptional activation of its target genes. TIRR mRNA expression levels negatively correlate with the expression of key p53 target genes in breast and prostate cancers. Further, TIRR loss is selectively not tolerated in p53-proficient tumors. Therefore, we establish that TIRR is an important inhibitor of the 53BP1-p53 complex.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Proteínas de Unión al ARN / Linaje de la Célula / Proteína 1 de Unión al Supresor Tumoral P53 Límite: Humans Idioma: En Revista: Mol Cell Asunto de la revista: BIOLOGIA MOLECULAR Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Proteínas de Unión al ARN / Linaje de la Célula / Proteína 1 de Unión al Supresor Tumoral P53 Límite: Humans Idioma: En Revista: Mol Cell Asunto de la revista: BIOLOGIA MOLECULAR Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos