TY - JOUR

T1 - Cockayne syndrome group A and B proteins function in rRNA transcription through nucleolin regulation

AU - Okur, Mustafa N

AU - Lee, Jong-Hyuk

AU - Osmani, Wasif

AU - Kimura, Risako

AU - Demarest, Tyler G

AU - Croteau, Deborah L

AU - Bohr, Vilhelm A

N1 - Published by Oxford University Press on behalf of Nucleic Acids Research 2020.

PY - 2020/3/18

Y1 - 2020/3/18

N2 - 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.

AB - 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.

KW - Cell Line

KW - Cockayne Syndrome/genetics

KW - DNA Helicases/metabolism

KW - DNA Repair Enzymes/metabolism

KW - DNA, Ribosomal/genetics

KW - Gene Expression Regulation

KW - Humans

KW - Models, Biological

KW - Phosphoproteins/genetics

KW - Poly-ADP-Ribose Binding Proteins/metabolism

KW - Protein Binding

KW - RNA, Ribosomal/genetics

KW - RNA-Binding Proteins/genetics

KW - Transcription Factors/metabolism

KW - Transcription, Genetic

U2 - 10.1093/nar/gkz1242

DO - 10.1093/nar/gkz1242

M3 - Journal article

C2 - 31970402

VL - 48

SP - 2473

EP - 2485

JO - Nucleic Acids Research

JF - Nucleic Acids Research

SN - 0305-1048

IS - 5

ER -