PUBLICATION

Zebrafish Models for Dyskeratosis Congenita Reveal Critical Roles of p53 Activation Contributing to Hematopoietic Defects through RNA Processing

Authors
Zhang, Y., Morimoto, K., Danilova, N., Zhang, B., and Lin, S.
ID
ZDB-PUB-120203-6
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
CTD
22299032
Abstract

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.

Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping