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

Ying Zhang,Kenji Morimoto,Shuo Lin,Bo Zhang,Nadia Danilova,Arthur J Lustig

doi:10.1371/journal.pone.0030188

Ying Zhang, Kenji Morimoto + Show 4 more

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https://doi.org/10.1371/journal.pone.0030188

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Journal: PloS one	Publication Date: Jan 27, 2012
Citations: 78	License type: CC BY 4.0

Affiliation: Peking University, University of California, Los Angeles

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.

Highlights

Dyskeratosis congenita (DC) is a rare bone marrow failure syndrome associated with abnormal skin pigmentation, nail dystrophy, mucosal leukoplakia, pulmonary fibrosis, and an increased susceptibility to both hematopoietic and solid cancers [1]. 85% of DC patients experience bone marrow failure that accounts for 80% of all DC-related mortality [2]
The goal of this study is to reveal the cause of bone marrow failure in DC
Mutations of several components of telomerase and shelterin complexes have been found in DC patients and in many cases telomere shortening is reported

Summary

Introduction

Dyskeratosis congenita (DC) is a rare bone marrow failure syndrome associated with abnormal skin pigmentation, nail dystrophy, mucosal leukoplakia, pulmonary fibrosis, and an increased susceptibility to both hematopoietic and solid cancers [1]. 85% of DC patients experience bone marrow failure that accounts for 80% of all DC-related mortality [2]. Dyskeratosis congenita (DC) is a rare bone marrow failure syndrome associated with abnormal skin pigmentation, nail dystrophy, mucosal leukoplakia, pulmonary fibrosis, and an increased susceptibility to both hematopoietic and solid cancers [1]. Discovery that the telomerase complex gene DKC1 was mutated in a subset of DC patients provided the first insight into a potential mechanism [3,4]. DKC1 encodes dyskerin, a pseudouridine synthase that complexes with box H/ACA small nuclear RNAs involved in posttranscriptional modification of ribosomal RNA (rRNA) through conversion of uridine (U) to pseudouridine (Y). Mutations in the catalytic domain of dyskerin lead to Hoyeraal-Hreidarsson syndrome resulting in a severe form of DC including immunodeficiency, growth retardation, and microcephaly. Dyskerin is associated with the RNA component of telomerase that contains an H/ACA RNA motif. Telomere shortening is associated with aging and genomic instability whose impact is widespread-healthy individuals with shorter telomeres possess a higher lifetime incidence of cancers [5] and shortened telomeres are associated with diverse pathologies including psychiatric disease [6], cardiovascular disease [7], idiopathic pulmonary fibrosis [8], and diabetes [9]

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