Published on July 15, 2005 in Hum Mol Genet volume 14(14).

PubMed ID: 15930015

DOI: ddi208

Abstract:

Treacher Collins syndrome (TCS) is characterized by defects in craniofacialdevelopment, which results from mutations in the TCOF1 gene. TCOF1 encodes thenucleolar phosphoprotein treacle, which interacts with upstream binding factor (UBF)and affects transcription of the ribosomal DNA gene. The present study showsparticipation of treacle in the 2'-O-methylation of pre-rRNA. Antisense-mediateddown-regulation of treacle expression in Xenopus laevis oocytes reduced2'-O-methylation of pre-rRNA. Analysis of RNA isolated from wild-type and Tcof1+/-heterozygous mice embryos from strains that exhibit a lethal phenotype showedsignificant reduction in 2'-O-methylation at nucleotide C463 of 18S rRNA. The levelof pseudouridylation of U1642 of 18S rRNA from the same RNA samples was not affectedsuggesting specificity. There is no significant difference in rRNA methylationbetween wild-type and heterozygous embryos of DBA x BALB/c mice, which have noobvious craniofacial phenotype. The function of treacle in pre-rRNA methylation ismost likely mediated by its direct physical interaction with NOP56, a component ofthe ribonucleoprotein methylation complex. Although treacle co-localizes with UBFthroughout mitosis, it co-localizes with NOP56 and fibrillarin, a putative methyltransferase, only during telophase when rDNA gene transcription and pre-rRNAmethylation are known to commence. These observations suggest that treacle mightlink RNA polymerase I-catalyzed transcription and post-transcriptional modificationof pre-rRNA. We hypothesize that haploinsufficiency of treacle in TCS patientsresults in inhibition of production of properly modified mature rRNA in addition toinhibition of rDNA gene transcription, which consequently affects proliferation andproper differentiation of specific embryonic cells during development.