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

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; Stephen J Smerdon; Jiri Lukas; Manuel Stucki

doi:10.1038/ncb3007

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

Nat Cell Biol. 2014 Aug;16(8):792-803. doi: 10.1038/ncb3007. Epub 2014 Jul 27.

Authors

Dorthe H Larsen¹, Flurina Hari², Julie A Clapperton³, Myriam Gwerder⁴, Katrin Gutsche⁴, Matthias Altmeyer⁵, Stephanie Jungmichel⁵, Luis I Toledo⁵, Daniel Fink⁴, Maj-Britt Rask⁵, Merete Grøfte⁵, Claudia Lukas⁵, Michael L Nielsen⁵, Stephen J Smerdon³, Jiri Lukas⁵, Manuel Stucki⁶

Affiliations

¹ 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.
² Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland.
³ MRC National Institute of Medical Research, Division of Protein Structure, The Ridgeway, Mill Hill, London NW7 1AA, UK.
⁴ Department of Gynecology, University Hospital and University of Zurich, Wagistrasse 14, CH-8952 Schlieren, Switzerland.
⁵ The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Faculty of Health and Medical Sciences, Blegdamsvej 3B DK-2200, Copenhagen, Denmark.
⁶ 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.

PMID: 25064736
PMCID: PMC4962910
DOI: 10.1038/ncb3007

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

Cell Cycle Proteins
Multiprotein Complexes
NBN protein, human
Nuclear Proteins
Phosphoproteins
RNA, Ribosomal
Recombinant Fusion Proteins
TCOF1 protein, human
Green Fluorescent Proteins
RNA Polymerase I

Abstract

Publication types

MeSH terms

Substances

Grants and funding