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.
Original language | English |
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Pages (from-to) | 792-803 |
Number of pages | 12 |
Journal | Nature Cell Biology |
Volume | 16 |
Issue number | 8 |
Early online date | 27 Jul 2014 |
DOIs | |
Publication status | Published - 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