2. Academic Validation
  3. Treacle controls the nucleolar response to rDNA breaks via TOPBP1 recruitment and ATR activation

Treacle controls the nucleolar response to rDNA breaks via TOPBP1 recruitment and ATR activation

  • Nat Commun. 2020 Jan 8;11(1):123. doi: 10.1038/s41467-019-13981-x.
Clémence Mooser 1,  Ioanna-Eleni Symeonidou 1,  Pia-Amata Leimbacher 1,  Alison Ribeiro 1,  Ann-Marie K Shorrocks 2 3,  Stephanie Jungmichel 4,  Sara C Larsen 4,  Katja Knechtle 1,  Arti Jasrotia 1,  Diana Zurbriggen 1,  Alain Jeanrenaud 1,  Colin Leikauf 1,  Daniel Fink 1,  Michael L Nielsen 4,  Andrew N Blackford 2 3,  Manuel Stucki 5
Affiliations

Affiliations

  • 1 Department of Gynecology, University of Zurich, Wagistrasse 14, CH-8952, Schlieren, Switzerland.
  • 2 Department of Oncology, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.
  • 3 Cancer Research UK/Medical Research Council Oxford Institute for Radiation Oncology, University of Oxford, Oxford, OX3 7DQ, UK.
  • 4 The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Faculty of Health and Medical Sciences, Bledgamsvej 3B DK-2200, Copenhagen, Denmark.
  • 5 Department of Gynecology, University of Zurich, Wagistrasse 14, CH-8952, Schlieren, Switzerland. [email protected].
PMID: 31913317 DOI: 10.1038/s41467-019-13981-x
Abstract

Induction of DNA double-strand breaks (DSBs) in ribosomal DNA (rDNA) repeats is associated with ATM-dependent repression of ribosomal RNA synthesis and large-scale reorganization of nucleolar architecture, but the signaling events that regulate these responses are largely elusive. Here we show that the nucleolar response to rDNA breaks is dependent on both ATM and ATR activity. We further demonstrate that ATM- and NBS1-dependent recruitment of TOPBP1 in the nucleoli is required for inhibition of ribosomal RNA synthesis and nucleolar segregation in response to rDNA breaks. Mechanistically, TOPBP1 recruitment is mediated by phosphorylation-dependent interactions between three of its BRCT domains and conserved phosphorylated Ser/Thr residues at the C-terminus of the nucleolar phosphoprotein Treacle. Our data thus reveal an important cooperation between TOPBP1 and Treacle in the signaling cascade that triggers transcriptional inhibition and nucleolar segregation in response to rDNA breaks.

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