Dysregulation of H/ACA ribonucleoprotein components in chronic lymphocytic leukemia

Santos, Patricia Carolina Dos; Panero, Julieta; Stanganelli, Carmen; Nagore, Virginia Palau; Stella, Flavia; Bezares, Raimundo F.; Slavutsky, Irma

doi:10.1371/journal.pone.0179883

Cited by 12 publications

(12 citation statements)

References 46 publications

(60 reference statements)

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“…Given this, we postulate that deficiencies in any of these four genes will impart significant G4 ligand sensitivity for a range of cell types and/or with other G4 ligands. As GAR1-deficiencies are implicated in chronic lymphocytic leukaemia and contribute to telomere dysfunction (Dos Santos et al, 2017), we suggest that this cancer may be acutely sensitive to G4-stabilisation by small molecules.…”

Section: Discussionmentioning

confidence: 88%

Genetic interactions of G-quadruplexes in humans

Zyner

Mulhearn

Adhikari

et al. 2019

eLife

106

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G-quadruplexes (G4) are alternative nucleic acid structures involved in transcription, translation and replication. Aberrant G4 formation and stabilisation is linked to genome instability and cancer. G4 ligand treatment disrupts key biological processes leading to cell death. To discover genes and pathways involved with G4s and gain mechanistic insights into G4 biology, we present the first unbiased genome-wide study to systematically identify human genes that promote cell death when silenced by shRNA in the presence of G4-stabilising small molecules. Many novel genetic vulnerabilities were revealed opening up new therapeutic possibilities in cancer, which we exemplified by an orthogonal pharmacological inhibition approach that phenocopies gene silencing. We find that targeting the WEE1 cell cycle kinase or USP1 deubiquitinase in combination with G4 ligand treatment enhances cell killing. We also identify new genes and pathways regulating or interacting with G4s and demonstrate that the DDX42 DEAD-box helicase is a newly discovered G4-binding protein.

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Section: Discussionmentioning

confidence: 88%

Genetic interactions of G-quadruplexes in humans

Zyner

Mulhearn

Adhikari

et al. 2019

eLife

106

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“…Therefore, reduced dyskerin protein in the context of the excessive cellular division in ECs may contribute to genomic instability that is known to be present, particularly in more advanced ECs. Dyskerin deficiency may also contribute to carcinogenesis by adversely influencing the translational machinery via affecting the balance in ribosomal proteins [ 33 ] and by modifying the splicing of specific pre-mRNAs, or by altering the level of certain snoRNAs [ 40 , 41 ]. These mechanistic aspects need to be examined in future studies.…”

Section: Discussionmentioning

confidence: 99%

Aberrant Dyskerin Expression Is Related to Proliferation and Poor Survival in Endometrial Cancer

Alnafakh

Saretzki

Midgley

et al. 2021

Cancers

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Dyskerin is a core-component of the telomerase holo-enzyme, which elongates telomeres. Telomerase is involved in endometrial epithelial cell proliferation. Most endometrial cancers (ECs) have high telomerase activity; however, dyskerin expression in human healthy endometrium or in endometrial pathologies has not been investigated yet. We aimed to examine the expression, prognostic relevance, and functional role of dyskerin in human EC. Endometrial samples from a cohort of 175 women were examined with immunohistochemistry, immunoblotting, and qPCR. The EC cells were transfected with Myc-DDK-DKC1 plasmid and the effect of dyskerin overexpression on EC cell proliferation was assessed by flow cytometry. Human endometrium expresses dyskerin (DKC1) and dyskerin protein levels are significantly reduced in ECs when compared with healthy postmenopausal endometrium. Low dyskerin immunoscores were potentially associated with worse outcomes, suggesting a possible prognostic relevance. Cancer Genome Atlas (TCGA) ECs dataset (n = 589) was also interrogated. The TCGA dataset further confirmed changes in DKC1 expression in EC with prognostic significance. Transient dyskerin overexpression had a negative effect on EC cell proliferation. Our data demonstrates a role for dyskerin in normal endometrium for the first time and confirms aberrant expression with possible prognostic relevance in EC. Interventions aimed at modulating dyskerin levels may provide novel therapeutic options in EC.

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“…The underlying molecular mechanisms of ribosomal modifications in various human diseases including malignancy are diverse and not fully understood [32][33][34]. Previous studies on neuroblastoma and lymphocytic leukemia demonstrated that snoRNP signature displayed highly significant prognostic value and was an independent predictor of poor prognosis through its effect on genomic stability and telomere maintenance [10,11].…”

Section: Discussionmentioning

confidence: 99%

“…(snoRNP) complexes [7]. Dysregulation of snoRNPs can influence the development and progression of various human diseases such as Prader Willi syndrome, some metabolic stress disorders, and several types of cancer [8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Nucleolar protein 10 (NOP10) predicts poor prognosis in invasive breast cancer

Elsharawy

Althobiti

Mohammed

et al. 2020

Breast Cancer Res Treat

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Purpose Nucleolar protein 10 (NOP10) is required for ribosome biogenesis and telomere maintenance and plays a key role in carcinogenesis. This study aims to evaluate the clinical and prognostic significance of NOP10 in breast cancer (BC). Methods NOP10 expression was assessed at mRNA level employing the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) (n = 1980) and Cancer Genome Atlas (TCGA) BC cohorts (n = 854). Protein expression was evaluated on tissue microarray of a large BC cohort (n = 1081) using immunohistochemistry. The correlation between NOP10 expression, clinicopathological parameters and patient outcome was assessed. Results NOP10 expression was detected in the nucleus and nucleolus of the tumour cells. At the transcriptomic and proteomic levels, NOP10 was significantly associated with aggressive BC features including high tumour grade, high nucleolar score and poor Nottingham Prognostic Index. High NOP10 protein expression was an independent predictor of poor outcome in the whole cohort and in triple-negative BC (TNBC) class (p = 0.002 & p = 0.014, respectively). In chemotherapy- treated patients, high NOP10 protein expression was significantly associated with shorter survival (p = 0.03) and was predictive of higher risk of death (p = 0.028) and development of distant metastasis (p = 0.02) independent of tumour size, nodal stage and tumour grade. Conclusion High NOP10 expression is a poor prognostic biomarker in BC and its expression can help in predicting chemotherapy resistance. Functional assessments are necessary to decipher the underlying mechanisms and to reveal its potential therapeutic values in various BC subtypes especially in the aggressive TNBC class.

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Dysregulation of H/ACA ribonucleoprotein components in chronic lymphocytic leukemia

Cited by 12 publications

References 46 publications

Genetic interactions of G-quadruplexes in humans

Genetic interactions of G-quadruplexes in humans

Aberrant Dyskerin Expression Is Related to Proliferation and Poor Survival in Endometrial Cancer

Nucleolar protein 10 (NOP10) predicts poor prognosis in invasive breast cancer

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