Cockayne syndrome group A and B proteins function in rRNA transcription through nucleolin regulation

Research output: Contribution to journalJournal articleResearchpeer-review

  • Mustafa N Okur
  • Jong-Hyuk Lee
  • Wasif Osmani
  • Risako Kimura
  • Tyler G Demarest
  • Deborah L Croteau
  • Bohr, Vilhelm

Cockayne Syndrome (CS) is a rare neurodegenerative disease characterized by short stature, accelerated aging and short lifespan. Mutations in two human genes, ERCC8/CSA and ERCC6/CSB, are causative for CS and their protein products, CSA and CSB, while structurally unrelated, play roles in DNA repair and other aspects of DNA metabolism in human cells. Many clinical and molecular features of CS remain poorly understood, and it was observed that CSA and CSB regulate transcription of ribosomal DNA (rDNA) genes and ribosome biogenesis. Here, we investigate the dysregulation of rRNA synthesis in CS. We report that Nucleolin (Ncl), a nucleolar protein that regulates rRNA synthesis and ribosome biogenesis, interacts with CSA and CSB. In addition, CSA induces ubiquitination of Ncl, enhances binding of CSB to Ncl, and CSA and CSB both stimulate the binding of Ncl to rDNA and subsequent rRNA synthesis. CSB and CSA also increase RNA Polymerase I loading to the coding region of the rDNA and this is Ncl dependent. These findings suggest that CSA and CSB are positive regulators of rRNA synthesis via Ncl regulation. Most CS patients carry mutations in CSA and CSB and present with similar clinical features, thus our findings provide novel insights into disease mechanism.

Original languageEnglish
JournalNucleic Acids Research
Issue number5
Pages (from-to)2473-2485
Number of pages13
Publication statusPublished - 18 Mar 2020

    Research areas

  • Cell Line, Cockayne Syndrome/genetics, DNA Helicases/metabolism, DNA Repair Enzymes/metabolism, DNA, Ribosomal/genetics, Gene Expression Regulation, Humans, Models, Biological, Phosphoproteins/genetics, Poly-ADP-Ribose Binding Proteins/metabolism, Protein Binding, RNA, Ribosomal/genetics, RNA-Binding Proteins/genetics, Transcription Factors/metabolism, Transcription, Genetic

ID: 257866222