Cockayne syndrome group A and B proteins function in rRNA transcription through nucleolin regulation.
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
Nucleolin
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
18 03 2020
18 03 2020
Historique:
accepted:
31
12
2019
revised:
30
12
2019
received:
21
11
2018
pubmed:
24
1
2020
medline:
19
5
2020
entrez:
24
1
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31970402
pii: 5714264
doi: 10.1093/nar/gkz1242
pmc: PMC7049711
doi:
Substances chimiques
DNA, Ribosomal
0
ERCC8 protein, human
0
Phosphoproteins
0
Poly-ADP-Ribose Binding Proteins
0
RNA, Ribosomal
0
RNA-Binding Proteins
0
Transcription Factors
0
DNA Helicases
EC 3.6.4.-
ERCC6 protein, human
EC 3.6.4.12
DNA Repair Enzymes
EC 6.5.1.-
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2473-2485Informations de copyright
Published by Oxford University Press on behalf of Nucleic Acids Research 2020.
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