Mapping and Characterization of the X-Linked Dyskeratosis Congenita (DKC) Gene

Hassock, Sheila; Vetrie, David; Giannelli, F.

doi:10.1006/geno.1998.5600

Cited by 32 publications

(17 citation statements)

References 29 publications

(31 reference statements)

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“…RT-PCR experiments revealed that expression of the 1.6-kb AtNAP57 transcript is ubiquitous (Fig. 1A), as is the case for mammalian dyskerin (16). AtNAP57 mRNA translates to a highly basic protein with a molecular mass of 63 kDa.…”

Section: Resultsmentioning

confidence: 87%

Dyskerin Is a Component of the Arabidopsis Telomerase RNP Required for Telomere Maintenance

Kannan

Nelson

Shippen

2008

Molecular and Cellular Biology

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Dyskerin binds the H/ACA box of human telomerase RNA and is a core telomerase subunit required for RNP biogenesis and enzyme function in vivo. Missense mutations in dyskerin result in dyskeratosis congenita, a complex syndrome characterized by bone marrow failure, telomerase enzyme deficiency, and progressive telomere shortening. Here we demonstrate that dyskerin also contributes to telomere maintenance in Arabidopsis thaliana. We report that both AtNAP57, the Arabidopsis dyskerin homolog, and AtTERT, the telomerase catalytic subunit, accumulate in the plant nucleolus, and AtNAP57 associates with active telomerase RNP particles in an RNA-dependent manner. Furthermore, AtNAP57 interacts in vitro with AtPOT1a, a novel component of Arabidopsis telomerase. Although a null mutation in AtNAP57 is lethal, AtNAP57, like AtTERT, is not haploinsufficient for telomere maintenance in Arabidopsis. However, introduction of an AtNAP57 allele containing a T66A mutation decreased telomerase activity in vitro, disrupted telomere length regulation on individual chromosome ends in vivo, and established a new, shorter telomere length set point. These results imply that T66A NAP57 behaves as a dominant-negative inhibitor of telomerase. We conclude that dyskerin is a conserved component of the telomerase RNP complex in higher eukaryotes that is required for maximal enzyme activity in vivo.

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Section: Resultsmentioning

confidence: 87%

Dyskerin Is a Component of the Arabidopsis Telomerase RNP Required for Telomere Maintenance

Kannan

Nelson

Shippen

2008

Molecular and Cellular Biology

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Section: Resultsmentioning

confidence: 99%

“…Both MPP1 and factor VIII genes are transcribed in the same orientation from telomere to centromere (20). Interestingly, the gene for X-linked dyskerotosis congenita (dyskerin/DKC) lies tail to tail with MPP1 gene on Xq28 (20). Patients with dyskeratosis congenita display increased susceptibility to cancer particularly affecting the progenitors in the skin and bone marrow (21).…”

Section: Resultsmentioning

confidence: 99%

Erythrocyte scaffolding protein p55/MPP1 functions as an essential regulator of neutrophil polarity

Quinn

Welch

Kim

et al. 2009

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

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As mediators of innate immunity, neutrophils respond to chemoattractants by adopting a highly polarized morphology. Efficient chemotaxis requires the formation of one prominent pseudopod at the cell front characterized by actin polymerization, while local inhibition suppresses the formation of rear and lateral protrusions. This asymmetric control of signaling pathways is required for directional migration along a chemotactic gradient. Here, we identify the MAGUK protein p55/MPP1 as a mediator of the frontness signal required for neutrophil polarization. We developed a p55 knockout (p55 ؊/؊ ) mouse model, and demonstrate that p55 ؊/؊ neutrophils form multiple transient pseudopods upon chemotactic stimulation, and do not migrate efficiently in vitro. Upon agonist stimulation, p55 is rapidly recruited to the leading edge of neutrophils in mice and humans. Total F-actin polymerization, along with Rac1 and RhoA activation, appear to be normal in p55 ؊/؊ neutrophils. Importantly, phosphorylation of Akt is significantly decreased in p55 ؊/؊ neutrophils upon chemotactic stimulation. The activity of immunoprecipitated phosphatidylinositol 3-kinase ␥ (PI3K␥), responsible for chemoattractantinduced synthesis of PIP3 and Akt phosphorylation, is unperturbed in p55 ؊/؊ neutrophils. Although the total amount of PIP3 is normal in p55 ؊/؊ neutrophils, PIP3 is diffusely localized and forms punctate aggregates in activated p55 ؊/؊ neutrophils, as compared to its accumulation at the leading edge membrane in the wild type neutrophils. Together, these results show that p55 is required for neutrophil polarization by regulating Akt phosphorylation through a mechanism that is independent of PI3K␥ activity.Akt ͉ erythrocyte p55 ͉ MPP1 ͉ MAGUK

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“…Subsequent cloning of the entire open reading frame (ORF) and screening of other DC patients identified an additional five missense mutations [27]. Characterisation of the gene responsible for Xlinked DC, DKC1, revealed the gene consists of 15 exons [28,29], that it is transcribed into an ~2.5 kb messenger RNA that is translated into a 514 aa/~57 kDa protein, dyskerin, which is ubiquitously expressed in adult and foetal tissues [27] (fig. 3).…”

Section: X-linked DC Genetic Localisation Of the X-linked Gene Dkc1mentioning

confidence: 99%

Human Genome and Diseases:�Dyskeratosis congenita

Marrone¹,

Mason²

2003

Cellular and Molecular Life Sciences (CMLS)

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Dyskeratosis congenita is an inherited skin and bone marrow failure syndrome. There are X-linked, autosomal dominant and autosomal recessive forms of the disease. The X-linked form is due to mutations in the DKC1 gene at Xq28. The encoded protein, dyskerin, is a component of both small nucleolar ribonuclear protein particles and the telomerase complex. Mutations in DKC1 mainly lead to amino acid substitutions. The autosomal dominant form of the disease is due to mutations in hTR, the RNA component of telomerase, making it likely that the disease is due to defective telomerase activity. Mutations in hTR are predicted to either disrupt secondary structure or alter the template region. The gene or genes involved in the recessive forms of the disease remain elusive, though genes whose products are required for telomere maintenance are strong candidates.

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Mapping and Characterization of the X-Linked Dyskeratosis Congenita (DKC) Gene

Cited by 32 publications

References 29 publications

Dyskerin Is a Component of the Arabidopsis Telomerase RNP Required for Telomere Maintenance

Dyskerin Is a Component of the Arabidopsis Telomerase RNP Required for Telomere Maintenance

Erythrocyte scaffolding protein p55/MPP1 functions as an essential regulator of neutrophil polarity

Human Genome and Diseases:�Dyskeratosis congenita

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