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

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

Cancer and Genomic Sciences

Research output: Contribution to journal › Article › peer-review

78 Citations (Scopus)

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
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	https://doi.org/10.1038/ncb3007
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

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Larsen, D. H., Hari, F., Clapperton, J. A., Gwerder, M., Gutsche, K., Altmeyer, M., Jungmichel, S., Toledo, L. I., Fink, D., Rask, M-B., Grøfte, M., Lukas, C., Nielsen, M. L., Smerdon, S. J., Lukas, J., & Stucki, M. (2014). The NBS1-Treacle complex controls ribosomal RNA transcription in response to DNA damage. Nature Cell Biology, 16(8), 792-803. Advance online publication. https://doi.org/10.1038/ncb3007

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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. ",

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",

author = "Larsen, {Dorthe H} and Flurina Hari and Clapperton, {Julie A} and Myriam Gwerder and Katrin Gutsche and Matthias Altmeyer and Stephanie Jungmichel and Toledo, {Luis I} and Daniel Fink and Maj-Britt Rask and Merete Gr{\o}fte and Claudia Lukas and Nielsen, {Michael L} and Smerdon, {Stephen J} and Jiri Lukas and Manuel Stucki",

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AU - Gutsche, Katrin

AU - Altmeyer, Matthias

AU - Jungmichel, Stephanie

AU - Toledo, Luis I

AU - Fink, Daniel

AU - Rask, Maj-Britt

AU - Grøfte, Merete

AU - Lukas, Claudia

AU - Nielsen, Michael L

AU - Smerdon, Stephen J

AU - Lukas, Jiri

AU - Stucki, Manuel

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AB - 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.

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KW - Cell Line

KW - Cell Nucleolus/metabolism

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KW - DNA Damage/genetics

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KW - HeLa Cells

KW - Humans

KW - Models, Biological

KW - Molecular Sequence Data

KW - Multiprotein Complexes/chemistry

KW - Nuclear Proteins/chemistry

KW - Phosphoproteins/chemistry

KW - Phosphorylation

KW - Protein Interaction Domains and Motifs

KW - RNA Polymerase I/metabolism

KW - RNA, Ribosomal/genetics

KW - Recombinant Fusion Proteins/genetics

KW - Transcription, Genetic

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DO - 10.1038/ncb3007

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JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 8

ER -

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

Abstract

Keywords

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