ZFIN ID: ZDB-PUB-120203-6
Zebrafish Models for Dyskeratosis Congenita Reveal Critical Roles of p53 Activation Contributing to Hematopoietic Defects through RNA Processing
Zhang, Y., Morimoto, K., Danilova, N., Zhang, B., and Lin, S.
Date: 2012
Source: PLoS One   7(1): e30188 (Journal)
Registered Authors: Danilova, Nadia, Lin, Shuo, Zhang, Bo, Zhang, Ying
Keywords: none
MeSH Terms:
  • Abnormalities, Multiple/genetics
  • Abnormalities, Multiple/pathology
  • Animals
  • Animals, Genetically Modified
  • Cell Cycle Proteins/genetics
  • Cell Cycle Proteins/physiology
  • Disease Models, Animal*
  • Dyskeratosis Congenita*/complications
  • Dyskeratosis Congenita*/genetics
  • Dyskeratosis Congenita*/metabolism
  • Dyskeratosis Congenita*/pathology
  • Embryo, Nonmammalian
  • Embryonic Development/genetics
  • Embryonic Development/physiology
  • Hematologic Diseases/etiology
  • Hematologic Diseases/genetics*
  • Hematologic Diseases/metabolism
  • Hematologic Diseases/pathology
  • Hematopoietic System/metabolism
  • Hematopoietic System/pathology
  • Nuclear Proteins/genetics
  • Nuclear Proteins/physiology
  • RNA Processing, Post-Transcriptional/genetics
  • RNA Processing, Post-Transcriptional/physiology*
  • Ribonucleoproteins, Small Nucleolar/genetics
  • Ribonucleoproteins, Small Nucleolar/physiology
  • Tumor Suppressor Protein p53/metabolism
  • Tumor Suppressor Protein p53/physiology*
  • Zebrafish*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/physiology
PubMed: 22299032 Full text @ PLoS One

Dyskeratosis congenita (DC) is a rare bone marrow failure syndrome in which hematopoietic defects are the main cause of mortality. The most studied gene responsible for DC pathogenesis is DKC1 while mutations in several other genes encoding components of the H/ACA RNP telomerase complex, which is involved in ribosomal RNA(rRNA) processing and telomere maintenance, have also been implicated. GAR1/nola1 is one of the four core proteins of the H/ACA RNP complex. Through comparative analysis of morpholino oligonucleotide induced knockdown of dkc1 and a retrovirus insertion induced mutation of GAR1/nola1 in zebrafish, we demonstrate that hematopoietic defects are specifically recapitulated in these models and that these defects are significantly reduced in a p53 null mutant background. We further show that changes in telomerase activity are undetectable at the early stages of DC pathogenesis but rRNA processing is clearly defective. Our data therefore support a model that deficiency in dkc1 and nola1 in the H/ACA RNP complex likely contributes to the hematopoietic phenotype through p53 activation associated with rRNA processing defects rather than telomerase deficiency during the initial stage of DC pathogenesis.