Targeted disruption of Dkc1, the gene mutated in X-linked dyskeratosis congenita, causes embryonic lethality in mice

He, Jun; Navarrete, Sandra; Jasinski, Murek; Vulliamy, Tom; Dokal, Inderjeet; Bessler, Monica; Mason, Philip J.

doi:10.1038/sj.onc.1205969

Cited by 95 publications

(88 citation statements)

References 26 publications

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“…Another bone marrow failure syndrome, dyskeratosis congenita, can be caused by mutations in different genes, one being DKC1 (encoding dyskerin) on the X chromosome. Ablation of dyskerin in male mice leads to apparent abnormality as early as E7.5 with subsequent embryo resorption (11). While dyskerin does localize to the nucleolus as well as the nucleoplasm, consistent with its predicted role in rRNA processing, interpretation of phenotype must also consider dyskerin's apparent role in telomere function (12).…”

Section: Discussionmentioning

confidence: 99%

Loss of the Mouse Ortholog of the Shwachman-Diamond Syndrome Gene (Sbds) Results in Early Embryonic Lethality

Zhang

Shi

Hui

et al. 2006

Molecular and Cellular Biology

107

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Mutations in SBDS are responsible for Shwachman-Diamond syndrome (SDS), a disorder with clinical features of exocrine pancreatic insufficiency, bone marrow failure, and skeletal abnormalities. SBDS is a highly conserved protein whose function remains largely unknown. We identified and investigated the expression pattern of the murine ortholog. Variation in levels was observed, but Sbds was found to be expressed in all embryonic stages and most adult tissues. Higher expression levels were associated with rapid proliferation. A targeted disruption of Sbds was generated in order to understand the consequences of its loss in an in vivo model. Consistent with recessive disease inheritance for SDS, Sbds ؉/؊ mice have normal phenotypes, indistinguishable from those of their wild-type littermates. However, the development of Sbds ؊/؊ embryos arrests prior to embryonic day 6.5, with muted epiblast formation leading to early lethality. This finding is consistent with the absence of patients who are homozygous for early truncating mutations. Sbds is an essential gene for early mammalian development, with an expression pattern consistent with a critical role in cell proliferation.

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Section: Discussionmentioning

confidence: 99%

Loss of the Mouse Ortholog of the Shwachman-Diamond Syndrome Gene (Sbds) Results in Early Embryonic Lethality

Zhang

Shi

Hui

et al. 2006

Molecular and Cellular Biology

107

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“…A null mutation has never been described in humans, and in mice it is not compatible with life (13). The mutations identified in DC patients therefore only impair but do not destroy dyskerin function.…”

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confidence: 99%

A pathogenic dyskerin mutation impairs proliferation and activates a DNA damage response independent of telomere length in mice

Gu¹,

Mason

2008

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

109

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Telomeres are nucleoprotein structures that cap the ends of chromosomes, protecting them from exonucleases and distinguishing them from double-stranded breaks. Their integrity is maintained by telomerase, an enzyme consisting of a reverse transcriptase, TERT and an RNA template, TERC, and other components, including the pseudouridine synthase, dyskerin, the product of the DKC1 gene. When telomeres become critically short, a p53-dependent pathway causing cell cycle arrest is induced that can lead to senescence, apoptosis, or, rarely to genomic instability and transformation. The same pathway is induced in response to DNA damage. DKC1 mutations in the disease dyskeratosis congenita are thought to act via this mechanism, causing growth defects in proliferative tissues through telomere shortening. Here, we show that pathogenic mutations in mouse Dkc1 cause a growth disadvantage and an enhanced DNA damage response in the context of telomeres of normal length. We show by genetic experiments that the growth disadvantage, detected by disparities in X-inactivation patterns in female heterozygotes, depends on telomerase. Hemizygous male mutant cells showed a strikingly enhanced DNA damage response via the ATM/p53 pathway after treatment with etoposide with a significant number of DNA damage foci colocalizing with telomeres in cytological preparations. We conclude that dyskerin mutations cause slow growth independently of telomere shortening and that this slow growth is the result of the induction of DNA damage. Thus, dyskerin interacts with telomerase and affects telomere maintenance independently of telomere length. dyskeratosis congenita ͉ heterozygous ͉ mosaic analysis ͉ telomerase ͉ ␣p53

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“…The gene encoding Cbf5 is essential in Eukarya (Jiang et al 1993;Meier and Blobel 1994;Heiss et al 1998;Phillips et al 1998;Giordano et al 1999;He et al 2002), which may be due to different roles of H/ACA RNPs in ribosome biogenesis, mRNA splicing, and telomere maintenance (Meier 2005;Karijolich and Yu 2008). The human homolog of Cbf5 is called dyskerin.…”

Section: Introductionmentioning

confidence: 99%

Structure–function relationships of archaeal Cbf5 during in vivo RNA-guided pseudouridylation

Majumder

Bosmeny

Gupta

2016

RNA

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In Eukarya and Archaea, in addition to protein-only pseudouridine (Ψ) synthases, complexes containing one guide RNA and four proteins can also produce Ψ. Cbf5 protein is the Ψ synthase in the complex. Previously, we showed that Ψ's at positions 1940, 1942, and 2605 of Haloferax volcanii 23S rRNA are absent in a cbf5-deleted strain, and a plasmid-borne copy of cbf5 can rescue the synthesis of these Ψ's. Based on published reports of the structure of archaeal Cbf5 complexed with other proteins and RNAs, we identified several potential residues and structures in H. volcanii Cbf5, which were expected to play important roles in pseudouridylation. We mutated these structures and determined their effects on Ψ production at the three rRNA positions under in vivo conditions. Mutations of several residues in the catalytic domain and certain residues in the thumb loop either abolished Ψ's or produced partial modification; the latter indicates a slower rate of Ψ formation. The universal catalytic aspartate of Ψ synthases could be replaced by glutamate in Cbf5. A conserved histidine, which is common to Cbf5 and TruB is not needed, but another conserved histidine of Cbf5 is required for the in vivo RNA-guided Ψ formation. We also identified a previously unreported novelty in the pseudouridylation activity of Cbf5 where a single stem-loop of a guide H/ACA RNA is used to produce two closely placed Ψ's and mutations of certain residues of Cbf5 abolished one of these two Ψ's. In summary, this first in vivo study identifies several structures of an archaeal Cbf5 protein that are important for its RNAguided pseudouridylation activity.

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Targeted disruption of Dkc1, the gene mutated in X-linked dyskeratosis congenita, causes embryonic lethality in mice

Cited by 95 publications

References 26 publications

Loss of the Mouse Ortholog of the Shwachman-Diamond Syndrome Gene (Sbds) Results in Early Embryonic Lethality

Loss of the Mouse Ortholog of the Shwachman-Diamond Syndrome Gene (Sbds) Results in Early Embryonic Lethality

A pathogenic dyskerin mutation impairs proliferation and activates a DNA damage response independent of telomere length in mice

Structure–function relationships of archaeal Cbf5 during in vivo RNA-guided pseudouridylation

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