The NBS1-Treacle complex controls ribosomal RNA transcription in response to DNA damage

Research output: Contribution to journalArticle

Authors

  • Dorthe H Larsen
  • Flurina Hari
  • Julie A Clapperton
  • Myriam Gwerder
  • Katrin Gutsche
  • Matthias Altmeyer
  • Stephanie Jungmichel
  • Luis I Toledo
  • Daniel Fink
  • Maj-Britt Rask
  • Merete Grøfte
  • Claudia Lukas
  • Michael L Nielsen
  • Jiri Lukas
  • Manuel Stucki

Colleges, School and Institutes

External organisations

  • 1] Department of Gynecology, University Hospital and University of Zurich, Wagistrasse 14, CH-8952 Schlieren, Switzerland [2] The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Faculty of Health and Medical Sciences, Blegdamsvej 3B DK-2200, Copenhagen, Denmark.
  • Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
  • MRC National Institute of Medical Research, Division of Protein Structure, The Ridgeway, Mill Hill, London NW7 1AA, UK.
  • Department of Gynecology, University Hospital and University of Zurich, Wagistrasse 14, CH-8952 Schlieren, Switzerland.
  • The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Faculty of Health and Medical Sciences, Blegdamsvej 3B DK-2200, Copenhagen, Denmark.
  • 1] Department of Gynecology, University Hospital and University of Zurich, Wagistrasse 14, CH-8952 Schlieren, Switzerland [2] Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.

Abstract

Chromosome breakage elicits transient silencing of ribosomal RNA synthesis, but the mechanisms involved remained elusive. Here we discover an in trans signalling mechanism that triggers pan-nuclear silencing of rRNA transcription in response to DNA damage. This is associated with transient recruitment of the Nijmegen breakage syndrome protein 1 (NBS1), a central regulator of DNA damage responses, into the nucleoli. We further identify TCOF1 (also known as Treacle), a nucleolar factor implicated in ribosome biogenesis and mutated in Treacher Collins syndrome, as an interaction partner of NBS1, and demonstrate that NBS1 translocation and accumulation in the nucleoli is Treacle dependent. Finally, we provide evidence that Treacle-mediated NBS1 recruitment into the nucleoli regulates rRNA silencing in trans in the presence of distant chromosome breaks.

Details

Original languageEnglish
Pages (from-to)792-803
Number of pages12
JournalNature Cell Biology
Volume16
Issue number8
Publication statusPublished - Aug 2014

Keywords

  • Amino Acid Sequence, Cell Cycle Proteins/chemistry, Cell Line, Cell Nucleolus/metabolism, Conserved Sequence, DNA Breaks, Double-Stranded, DNA Damage/genetics, Gene Silencing, Green Fluorescent Proteins/genetics, HEK293 Cells, HeLa Cells, Humans, Models, Biological, Molecular Sequence Data, Multiprotein Complexes/chemistry, Nuclear Proteins/chemistry, Phosphoproteins/chemistry, Phosphorylation, Protein Interaction Domains and Motifs, RNA Polymerase I/metabolism, RNA, Ribosomal/genetics, Recombinant Fusion Proteins/genetics, Transcription, Genetic