Correlation of dyskerin expression with active proliferation independent of telomerase

Alawi, Faizan; Lin, Ping; Ziober, Barry L.; Patel, Reena G.

doi:10.1002/hed.21579

Cited by 28 publications

(33 citation statements)

References 52 publications

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“…This is consistent with the G2/M delay which we previously observed in BCS patient lymphoblasts, as well as numerous reports of mitotic or cytokinetic defects in cells deficient in other ribosome biogenesis factors [24][25][26][27], reviewed in [28]. Many ribosomal biogenesis factors and prerRNA move from the nucleolus to the mitotic spindle or the perichromosomal layer during mitosis [29][30][31][32][33][34][35][36]. Furthermore, mutations in perichromosomal proteins have been shown to lead to increased binucleation following mitotic defects [37].…”

Section: Perichromosomal Localization Of Emg1 During Mitosis Underliesupporting

confidence: 84%

“…We previously described G2/M accumulation and slow proliferation rates in BCS patient lymphoblasts [4]. However, accumulation at G2/M and/or mitotic spindle defects have also been observed in other ribosome biogenesis disorders, including Shwachman-Diamond syndrome [35], Treacher Collins syndrome [34], X-linked dyskeratosis congenita [33,39], and North American Indian childhood cirrhosis [36]. The factors responsible for these disorders frequently re-localize to the mitotic spindle or the chromosome periphery during mitosis, similar to EMG1 (Fig.…”

Section: Discussionmentioning

confidence: 96%

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Growth arrest in the ribosomopathy, Bowen–Conradi syndrome, is due to dramatically reduced cell proliferation and a defect in mitotic progression

Armistead

Patel

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Bowen-Conradi syndrome (BCS) is a ribosomopathy characterized by severe developmental delay and growth failure that typically leads to death by one year of age. It is caused by a c.257A>G, p.D86G substitution in the ribosomal biogenesis protein, Essential for Mitotic Growth 1 (EMG1). We generated a knock-in of the D86G substitution in mice to characterize the effects of EMG1 deficiency, particularly in the brain, where EMG1 expression is high. Embryos homozygous for the mutation in Emg1 were small for gestational age with neural tube defects, and died between embryonic days 8.5 and 12.5. These embryos exhibited dramatically reduced cell proliferation, which we also detected in autopsy brain tissue and bone marrow of BCS patients, consistent with a requirement for high levels of EMG1 in tissues with rapid cell proliferation. In fibroblasts derived from the BCS mouse embryos, we detected a high proportion of binucleated cells, indicating that a mitotic defect underlies the growth arrest in BCS. These studies add to growing evidence of a link between ribosome biogenesis, mitotic progression, and brain development that is currently unexplored.

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Section: Perichromosomal Localization Of Emg1 During Mitosis Underliesupporting

confidence: 84%

Section: Discussionmentioning

confidence: 96%

Growth arrest in the ribosomopathy, Bowen–Conradi syndrome, is due to dramatically reduced cell proliferation and a defect in mitotic progression

Armistead

Patel

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…Thus we reasoned that any observed phenotype associated with dyskerin depletion would not be a result of accelerated telomere shortening. To further ensure this, we employed telomerase-negative U2OS cells which express relatively high levels of dyskerin [6, 15]. After 72 hrs, dyskerin expression was reduced more than 80-90% relative to the controls irrespective of the siRNA used (Fig.…”

Section: Resultsmentioning

confidence: 99%

Acute dyskerin depletion triggers cellular senescence and renders osteosarcoma cells resistant to genotoxic stress-induced apoptosis

Lin

Mobasher

Alawi

2014

Biochemical and Biophysical Research Communications

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Dyskerin is a conserved, nucleolar RNA-binding protein implicated in an increasing array of fundamental cellular processes. Germline mutation in the dyskerin gene (DKC1) is the cause of X-linked dyskeratosis congenita. Conversely, wild-type dyskerin is overexpressed in sporadic cancers, and high-levels may be associated with poor prognosis. It was previously reported that acute loss of dyskerin function via siRNA-mediated depletion slowed the proliferation of transformed cell lines. However, the mechanisms remained unclear. Using human U2OS osteosarcoma cells, we show that siRNA-mediated dyskerin depletion induced cellular senescence as evidenced by proliferative arrest, senescence-associated heterochromatinization and a senescence-associated molecular profile. Senescence can render cells resistant to apoptosis. Conversely, chromatin relaxation can reverse the repressive effects of senescence-associated heterochromatinization on apoptosis. To this end, genotoxic stress-induced apoptosis was suppressed in dyskerin-depleted cells. In contrast, agents that induce chromatin relaxation, including histone deacetylase inhibitors and the DNA intercalator chloroquine, sensitized dyskerin-depleted cells to apoptosis. Dyskerin is a core component of the telomerase complex and plays an important role in telomere homeostasis. Defective telomere maintenance resulting in premature senescence is thought to primarily underlie the pathogenesis of X-linked DC. Since U2OS cells are telomerase-negative, this leads us to conclude that loss of dyskerin function can also induce cellular senescence via mechanisms independent of telomere shortening.

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“…In general, rapidly proliferating cells express relatively high levels of dyskerin (Alawi and Lee 2007; Alawi and Lin 2011; Alawi et al 2011). Dyskerin mRNA is upregulated in an array of cancer types, and high levels may be associated with poor prognosis (Sieron et al 2009; Alawi et al 2011; von Stedingk et al 2013).…”

Section: Introductionmentioning

confidence: 99%

Differential requirements for H/ACA ribonucleoprotein components in cell proliferation and response to DNA damage

Lin

Mobasher

Hakakian

et al. 2015

Histochem Cell Biol

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H/ACA ribonucleoproteins (RNPs) are comprised of four conserved proteins, dyskerin, NHP2, NOP10, and GAR1, and a function-specifying, noncoding H/ACA RNA. H/ACA RNPs contribute to telomerase assembly and stabilization, and posttranscriptional processing of nascent ribosomal RNA and spliceosomal RNA. However, very little is known about the coordinated action of the four proteins in other biologic processes. As described herein, we observed a differential requirement for the proteins in cell proliferation and identified a possible reliance for these factors in regulation of specific DNA damage biomarkers. In particular, GAR1 expression was upregulated following exposure to all forms of genotoxic stress tested. In contrast, levels of the other proteins were either reduced or unaffected. Only GAR1 showed an altered subcellular localization with a shift from the nucleolus to the nucleoplasm after ultraviolet-C irradiation and doxorubicin treatments. Transient siRNA-mediated depletion of GAR1 and dyskerin arrested cell proliferation, whereas loss of either NHP2 or NOP10 had no effect. Finally, loss of dyskerin, GAR1, NHP2, and NOP10, respectively, limited the accumulation of DNA damage biomarkers. However, the individual responses were dependent upon the specific type of damage incurred. In general, loss of GAR1 had the most suppressive effect on the biomarkers tested. Since the specific responses to genotoxic stress, the contribution of each protein to cell proliferation, and the activation of DNA damage biomarkers were not equivalent, this suggests the possibility that at least some of the proteins, most notably GAR1, may potentially function independently of their respective roles within H/ACA RNP complexes.

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Correlation of dyskerin expression with active proliferation independent of telomerase

Cited by 28 publications

References 52 publications

Growth arrest in the ribosomopathy, Bowen–Conradi syndrome, is due to dramatically reduced cell proliferation and a defect in mitotic progression

Growth arrest in the ribosomopathy, Bowen–Conradi syndrome, is due to dramatically reduced cell proliferation and a defect in mitotic progression

Acute dyskerin depletion triggers cellular senescence and renders osteosarcoma cells resistant to genotoxic stress-induced apoptosis

Differential requirements for H/ACA ribonucleoprotein components in cell proliferation and response to DNA damage

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