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PMID: 15249688 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

The Treacher Collins syndrome (TCOF1) gene product is involved in ribosomal DNA gene transcription by interacting with upstream binding factor.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 101 ·No. 29 ·2004-07-20 ·Pages 10709-14

Valdez BC, Henning D, So RB, Dixon J, Dixon MJ

Abstract

Treacher Collins syndrome (TCS) is an autosomal dominant disorder characterized by an abnormality of craniofacial development that arises during early embryogenesis. TCS is caused by mutations in the gene TCOF1, which encodes the nucleolar phosphoprotein treacle. Even though the genetic alterations causing TCS have been uncovered, the mechanism underlying its pathogenesis and the function of treacle remain unknown. Here, we show that treacle is involved in ribosomal DNA gene transcription by interacting with upstream binding factor (UBF). Immunofluorescence labeling shows treacle and UBF colocalize to specific nucleolar organizer regions and cosegregate within nucleolar caps of actinomycin d-treated HeLa cells. Biochemical analysis shows the association of treacle and UBF with chromatin. Immunoprecipitation and the yeast two-hybrid system both suggest physical interaction of the two nucleolar phosphoproteins. Down-regulation of treacle expression using specific short interfering RNA results in inhibition of ribosomal DNA transcription and cell growth. A similar correlation is observed in Tcof(+/-) mouse embryos that exhibit craniofacial defects and growth retardation. Thus, treacle haploinsufficiency in TCS patients might result in abnormal development caused by inadequate ribosomal RNA production in the prefusion neural folds during the early stages of embryogenesis. The elucidation of a physiological function of treacle provides important information of relevance to the molecular dissection of the biochemical pathology of TCS.

MeSH Terms
Animals Cell Cycle/physiology Chromatin/metabolism DNA, Ribosomal/metabolism Dactinomycin/metabolism HeLa Cells Humans Intracellular Signaling Peptides and Proteins Mice Nuclear Proteins/genetics,metabolism Nucleolus Organizer Region/metabolism Phosphoproteins/genetics,metabolism Pol1 Transcription Initiation Complex Proteins/metabolism Protein Binding RNA, Small Interfering/genetics,metabolism Recombinant Fusion Proteins/genetics,metabolism Transcription, Genetic Two-Hybrid System Techniques
Chemicals
Chromatin DNA, Ribosomal Intracellular Signaling Peptides and Proteins Nuclear Proteins Phosphoproteins Pol1 Transcription Initiation Complex Proteins RNA, Small Interfering Recombinant Fusion Proteins TCOF1 protein, human Tcof1 protein, mouse transcription factor UBF Dactinomycin
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Valdez Benigno C
Department of Pharmacology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. bvaldez@bcm.tmc.edu
Henning Dale
So Rolando B
Dixon Jill
Dixon Michael J
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0402492101
Email
bvaldez@bcm.tmc.edu
Published
2004-07-20
Epub
2004-00-12
Pages
10709-14
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC489999
Subset
IM
Grants
NIDDK NIH HHS · R01 DK052341 · United States
NIDDK NIH HHS · DK52341 · United States
External Links
PubMed source DOI: 10.1073/pnas.0402492101 PMC Full Text View journal details
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