2. Academic Validation
  3. A role for Tau protein in maintaining ribosomal DNA stability and cytidine deaminase-deficient cell survival

A role for Tau protein in maintaining ribosomal DNA stability and cytidine deaminase-deficient cell survival

  • Nat Commun. 2017 Sep 25;8(1):693. doi: 10.1038/s41467-017-00633-1.
Elias Bou Samra 1 2 3,  Géraldine Buhagiar-Labarchède 1 2 3,  Christelle Machon 4 5,  Jérôme Guitton 4 6,  Rosine Onclercq-Delic 1 2 3,  Michael R Green 7,  Olivier Alibert 8,  Claude Gazin 8,  Xavier Veaute 9,  Mounira Amor-Guéret 10 11 12
Affiliations

Affiliations

  • 1 Institut Curie, PSL Research University, UMR 3348, Orsay, 91405, France.
  • 2 CNRS UMR 3348, Centre Universitaire, Orsay, 91405, France.
  • 3 Université Paris Sud, Université Paris-Saclay, Centre Universitaire, UMR 3348, Orsay, 91405, France.
  • 4 Laboratoire de Biochimie et Toxicologie, Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Pierre-Bénite, 69495, France.
  • 5 ISPB Faculté de Pharmacie, Laboratoire de Chimie Analytique, Université de Lyon, Université Lyon 1, Lyon, 69008, France.
  • 6 ISPB, Faculté de PharmacieLaboratoire de Toxicologie, Université de Lyon, Université Lyon 1, Lyon, 69008, France.
  • 7 Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, Massachusetts, 01605, USA.
  • 8 CEA-DRF-iRCM-LEFG-Genopole, Evry, 91057, France.
  • 9 CEA-DRF-iRCM-CIGEx, Fontenay-aux-Roses, 92265, France.
  • 10 Institut Curie, PSL Research University, UMR 3348, Orsay, 91405, France. mounira.amor@curie.fr.
  • 11 CNRS UMR 3348, Centre Universitaire, Orsay, 91405, France. mounira.amor@curie.fr.
  • 12 Université Paris Sud, Université Paris-Saclay, Centre Universitaire, UMR 3348, Orsay, 91405, France. mounira.amor@curie.fr.
PMID: 28947735 DOI: 10.1038/s41467-017-00633-1
Abstract

Cells from Bloom's syndrome patients display genome instability due to a defective BLM and the downregulation of cytidine deaminase. Here, we use a genome-wide RNAi-synthetic lethal screen and transcriptomic profiling to identify genes enabling BLM-deficient and/or cytidine deaminase-deficient cells to tolerate constitutive DNA damage and replication stress. We found a synthetic lethal interaction between cytidine deaminase and microtubule-associated protein Tau deficiencies. Tau is overexpressed in cytidine deaminase-deficient cells, and its depletion worsens genome instability, compromising cell survival. Tau is recruited, along with upstream-binding factor, to ribosomal DNA loci. Tau downregulation decreases upstream binding factor recruitment, ribosomal RNA synthesis, ribonucleotide levels, and affects ribosomal DNA stability, leading to the formation of a new subclass of human ribosomal ultrafine anaphase bridges. We describe here Tau functions in maintaining survival of cytidine deaminase-deficient cells, and ribosomal DNA transcription and stability. Moreover, our findings for Cancer tissues presenting concomitant cytidine deaminase underexpression and Tau upregulation open up new possibilities for anti-cancer treatment.Cytidine deaminase (CDA) deficiency leads to genome instability. Here the authors find a synthetic lethal interaction between CDA and the microtubule-associated protein Tau deficiencies, and report that Tau depletion affects rRNA synthesis, ribonucleotide pool balance, and rDNA stability.

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