Dyskeratosis Congenita and Cancer in Mice Deficient in Ribosomal RNA Modification

Ruggero, Davide; Grisendi, Silvia; Piazza, Francesco; Rego, Eduardo Magalhães; Mari, Francesca; Rao, Pulivarthi H.; Cordon‐Cardo, Carlos; Pandolfi, Pier Paolo

doi:10.1126/science.1079447

Cited by 382 publications

(364 citation statements)

References 21 publications

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“…6A) (41). Because DNA from an entire plant is analyzed, these results mean that individual telomere tracts are subjected to extremely tight regulation during plant growth and development (39). Strikingly, with T66A nap57 mutants, PETRA generates a complex profile of multiple sharp bands, indicating that telomere length is deregulated on individual chromosome ends.…”

Section: Discussionmentioning

confidence: 95%

“…One of the most commonly identified dyskerin mutations, A353V, perturbs rRNA pseudouridylation and also results in reduced levels of TR, decreased telomerase activity, and shorter telomeres in mouse embryonic stem cells (33). Similarly, hypomorphic mice that express low levels of dyskerin display the clinical symptoms of DC and exhibit shorter telomeres, but only in later generations (39). While rRNA processing is affected in some dyskerin mutants, the T66A mutation in humans appears to exclusively affect the telomerase-associated functions of dyskerin (32).…”

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confidence: 99%

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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: Discussionmentioning

confidence: 95%

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confidence: 99%

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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“…55 Further confusing the picture is a hypomorphic Dkc1 mutant mouse, which demonstrated impaired ribosomal RNA pseudo-uridylation before the onset of clinical features of DKC, whereas reductions in telomere length became evident only in later generations. 56 Although it is clear that telomeres play a significant role in the pathogenesis of DKC, there may be a distinct contribution from ribosomal defects. Ongoing work examining genotype/phenotype correlations and basic mechanisms will hopefully elucidate the true contributions of telomerase activity and impaired ribosomal biogenesis to the pathophysiology of DKC.…”

Section: Dyskeratosis Congenitamentioning

confidence: 99%

Ribosomopathies: human disorders of ribosome dysfunction

Narla

Ebert

2010

Blood

697

726

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Ribosomopathies compose a collection of disorders in which genetic abnormalities cause impaired ribosome biogenesis and function, resulting in specific clinical phenotypes. Congenital mutations in RPS19 and other genes encoding ribosomal proteins cause Diamond-Blackfan anemia, a disorder characterized by hypoplastic, macrocytic anemia. Mutations in other genes required for normal ribosome biogenesis have been implicated in other rare congenital syndromes, SchwachmanDiamond syndrome, dyskeratosis congenita, cartilage hair hypoplasia, and Treacher Collins syndrome. In addition, the 5q؊ syndrome, a subtype of myelodysplastic syndrome, is caused by a somatically acquired deletion of chromosome 5q, which leads to haploinsufficiency of the ribosomal protein RPS14 and an erythroid phenotype highly similar to Diamond-Blackfan anemia. Acquired abnormalities in ribosome function have been implicated more broadly in human malignancies. The p53 pathway provides a surveillance mechanism for protein translation as well as genome integrity and is activated by defects in ribosome biogenesis; this pathway appears to be a critical mediator of many of the clinical features of ribosomopathies. Elucidation of the mechanisms whereby selective abnormalities in ribosome biogenesis cause specific clinical syndromes will hopefully lead to novel therapeutic strategies for these diseases. Identification of ribosomal abnormalities in human diseaseIn 1999, Draptchinskaia et al reported recurrent mutations in a ribosomal protein gene, RPS19, in patients with Diamond-Blackfan anemia (DBA), a rare congenital bone marrow failure syndrome with a striking erythroid defect. 1 Since that initial discovery, mutations in a number of ribosomal proteins have been identified in up to 50% of patients with DBA. Moreover, other congenital syndromes have been linked to defective ribosome biogenesis, including Schwachman-Diamond syndrome (SDS), X-linked dyskeratosis congenita (DKC), cartilage hair hypoplasia (CHH), and Treacher Collins syndrome (TCS). 2 In the 5qϪ syndrome, a subtype of adult myelodysplastic syndrome, acquired haploinsufficiency for RPS14 resulting from an interstitial chromosomal deletion causes a severe refractory anemia. 3 Each of these disorders is associated with specific defects in ribosome biogenesis, which cause distinct clinical phenotypes, most often involving bone marrow failure and/or craniofacial or other skeletal defects. The disorders of ribosome dysfunction have become collectively known as ribosomopathies. Overview of ribosome biogenesisThe eukaryotic ribosome is composed of 40S and 60S subunits, which associate to form the translationally active 80S ribosome. This process requires the coordinated synthesis of 4 ribosomal RNAs (rRNAs), approximately 80 core ribosomal proteins, more than 150 associated proteins, and approximately 70 small nucleolar RNAs (snoRNAs). 4,5 The 40S subunit contains 18S rRNA and the 60S subunit contains 28S, 5.8S, and 5S rRNAs. In eukaryotes, assembly of rRNA and ribosomal proteins, along with assoc...

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“…In conjunction with chronic anemia and congenital abnormalities, Diamond-Blackfan anemia patients also harbor a predisposition to development of a number of cancers. Another example is dyskeratosis congenita, a rare X-linked condition characterized by accelerated aging and increased susceptibility to cancer (Ruggero et al, 2003). Individuals with this disorder harbor a mutation in the psuedouridine synthase gene DKC1, resulting in rRNA processing deficiency and the clinical onset of the disease.…”

Section: Nucleolar Stress and Human Diseasementioning

confidence: 99%

Ribosome biogenesis surveillance: probing the ribosomal protein-Mdm2-p53 pathway

2010

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Dyskeratosis Congenita and Cancer in Mice Deficient in Ribosomal RNA Modification

Cited by 382 publications

References 21 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

Ribosomopathies: human disorders of ribosome dysfunction

Ribosome biogenesis surveillance: probing the ribosomal protein-Mdm2-p53 pathway

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