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

Clémence Mooser, Ioanna-Eleni Symeonidou, Pia-Amata Leimbacher, Alison Ribeiro, Ann-Marie K. Shorrocks, Stephanie Jungmichel, Sara C. Larsen, Katja Knechtle, Arti Jasrotia, Diana Zurbriggen, Alain Jeanrenaud, Colin Leikauf, Daniel Fink, Michael L. Nielsen, Andrew N. Blackford and Manuel Stucki ()
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Clémence Mooser: University of Zurich
Ioanna-Eleni Symeonidou: University of Zurich
Pia-Amata Leimbacher: University of Zurich
Alison Ribeiro: University of Zurich
Ann-Marie K. Shorrocks: University of Oxford, John Radcliffe Hospital
Stephanie Jungmichel: University of Copenhagen, Faculty of Health and Medical Sciences
Sara C. Larsen: University of Copenhagen, Faculty of Health and Medical Sciences
Katja Knechtle: University of Zurich
Arti Jasrotia: University of Zurich
Diana Zurbriggen: University of Zurich
Alain Jeanrenaud: University of Zurich
Colin Leikauf: University of Zurich
Daniel Fink: University of Zurich
Michael L. Nielsen: University of Copenhagen, Faculty of Health and Medical Sciences
Andrew N. Blackford: University of Oxford, John Radcliffe Hospital
Manuel Stucki: University of Zurich

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-13981-x

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