scholarly journals Frequent Germline and Somatic Single Nucleotide Variants in the Promoter Region of the Ribosomal RNA Gene in Japanese Lung Adenocarcinoma Patients

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2409
Author(s):  
Riuko Ohashi ◽  
Hajime Umezu ◽  
Ayako Sato ◽  
Tatsuya Abé ◽  
Shuhei Kondo ◽  
...  
Keyword(s):  
Ribosomal Rna ◽  
Promoter Region ◽  
Ribosome Biogenesis ◽  
Genetic Disorders ◽  
Univariate Analysis ◽  
Rrna Gene ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Lung Adenocarcinomas

Ribosomal RNA (rRNA), the most abundant non-coding RNA species, is a major component of the ribosome. Impaired ribosome biogenesis causes the dysfunction of protein synthesis and diseases called “ribosomopathies,” including genetic disorders with cancer risk. However, the potential role of rRNA gene (rDNA) alterations in cancer is unknown. We investigated germline and somatic single-nucleotide variants (SNVs) in the rDNA promoter region (positions −248 to +100, relative to the transcription start site) in 82 lung adenocarcinomas (LUAC). Twenty-nine tumors (35.4%) carried germline SNVs, and eight tumors (9.8%) harbored somatic SNVs. Interestingly, the presence of germline SNVs between positions +1 and +100 (n = 12; 14.6%) was associated with significantly shorter recurrence-free survival (RFS) and overall survival (OS) by univariate analysis (p < 0.05, respectively), and was an independent prognostic factor for RFS and OS by multivariate analysis. LUAC cell line PC9, carrying rDNA promoter SNV at position +49, showed significantly higher ribosome biogenesis than H1650 cells without SNV. Upon nucleolar stress induced by actinomycin D, PC9 retained significantly higher ribosome biogenesis than H1650. These results highlight the possible functional role of SNVs at specific sites of the rDNA promoter region in ribosome biogenesis, the progression of LUAC, and their potential prognostic value.

scholarly journals Structural variant detection in cancer genomes: computational challenges and perspectives for precision oncology

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Ianthe A. E. M. van Belzen ◽  
Alexander Schönhuth ◽  
Patrick Kemmeren ◽  
Jayne Y. Hehir-Kwa
Keyword(s):  
Intratumor Heterogeneity ◽  
Precision Oncology ◽  
Single Nucleotide Variants ◽  
Full Spectrum ◽  
Single Nucleotide ◽  
Sequencing Technologies ◽  
Cancer Genomes ◽  
Genomic Aberrations

AbstractCancer is generally characterized by acquired genomic aberrations in a broad spectrum of types and sizes, ranging from single nucleotide variants to structural variants (SVs). At least 30% of cancers have a known pathogenic SV used in diagnosis or treatment stratification. However, research into the role of SVs in cancer has been limited due to difficulties in detection. Biological and computational challenges confound SV detection in cancer samples, including intratumor heterogeneity, polyploidy, and distinguishing tumor-specific SVs from germline and somatic variants present in healthy cells. Classification of tumor-specific SVs is challenging due to inconsistencies in detected breakpoints, derived variant types and biological complexity of some rearrangements. Full-spectrum SV detection with high recall and precision requires integration of multiple algorithms and sequencing technologies to rescue variants that are difficult to resolve through individual methods. Here, we explore current strategies for integrating SV callsets and to enable the use of tumor-specific SVs in precision oncology.

Genetics of Schizophrenia and Bipolar Disorder

2017 ◽  
Author(s):  
Alexander Charney ◽  
Pamela Sklar
Keyword(s):  
Bipolar Disorder ◽  
Copy Number ◽  
Psychotic Disorders ◽  
Copy Number Variants ◽  
Nucleotide Polymorphisms ◽  
Common Variants ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Number Variation

Schizophrenia and bipolar disorder are the classic psychotic disorders. Both diseases are strongly familial, but have proven recalcitrant to genetic methodologies for identifying the etiology until recently. There is now convincing genetic evidence that indicates a contribution of many DNA changes to the risk of becoming ill. For schizophrenia, there are large contributions of rare copy number variants and common single nucleotide variants, with an overall highly polygenic genetic architecture. For bipolar disorder, the role of copy number variation appears to be much less pronounced. Specific common single nucleotide polymorphisms are associated, and there is evidence for polygenicity. Several surprises have emerged from the genetic data that indicate there is significantly more molecular overlap in copy number variants between autism and schizophrenia, and in common variants between schizophrenia and bipolar disorder.

scholarly journals 2466. What’s Lurking in the Drain? Serial transmission of NDM-1Klebsiella pneumoniae to patients admitted 9 months apart to the same ICU room

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S854-S854
Author(s):  
Becky A Smith ◽  
Amy Mathers ◽  
Shireen Kotay ◽  
Hardik Parikh ◽  
Katie E Barry ◽  
...  
Keyword(s):  
Environmental Samples ◽  
Index Patient ◽  
Point Prevalence ◽  
Secondary Case ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Environmental Investigation ◽  
Long Duration ◽  
Rectal Colonization

Abstract Background We evaluated the role of an in-room sink in NDM-1 K. pneumoniae (NDMKP) transmission. Methods In October 2017, Infection Prevention (IP) initiated weekly point prevalence rectal screening cultures in 4 ICUs. In 3/2018, IP launched an epidemiologic and environmental investigation following identification of a patient with NDMKP rectal colonization. Environmental samples including swabs of biofilm from drains and water from p-traps were obtained from the in-room sink. Illumina whole-genome sequencing (WGS) was performed on all NDMKP patient and environmental isolates. Single nucleotide variants (SNVs) were identified against the reference Klebsiella pneumoniae strain MLST15 (NZ_CP022127), and isolates within 150 SNVs of each other were considered to be genomically related. Results Two patients were identified with NDMKP infection or colonization between July 2017 and March 2018. The index patient had prolonged hospitalization and developed NDMKP bacteremia on hospital day (HD) 30. Approximately 9 months later, the second patient was admitted to the same ICU room that had been occupied by the index patient for 13 days and was identified to have NDMKP rectal colonization on HD 5. Environmental samples from the in-room sink of the ICU room grew NDMKP. WGS demonstrated relatedness between NDMKP isolates from the 2 patients (112 SNV), the index patient and the sink (52 SNV), and the second patient and the sink (80 SNV). The in-room sink was replaced in 4/18 and no further cases of NDMKP infection or colonization have been identified at DUH in over 12 months. Conclusion We report an NDM-1 K. pneumoniae transmission event possibly related to a contaminated in-room sink drain. Remarkably, 9 months elapsed between the index case and the second case, with no additional interim cases detected on weekly point-prevalence screening or clinical cultures. The long duration of time between and the index patient, secondary case, and sink culture may explain why WGS showed relatedness but not identical clones. Education around sink use, design, and more effective cleaning strategies are needed to mitigate environment-to-patient transmission of CRO. Disclosures All authors: No reported disclosures.

scholarly journals The role of single-nucleotide variants of the energy metabolism-linked genes SIRT3, PPARGC1A and APOE in amyotrophic lateral sclerosis risk

2016 ◽  
Vol 91 (6) ◽  
pp. 301-309 ◽  
Author(s):  
Diego Albani ◽  
Elisabetta Pupillo ◽  
Elisa Bianchi ◽  
Armando Chierchia ◽  
Rosalba Martines ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Energy Metabolism ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Lateral Sclerosis

scholarly journals Structure and function of ribosomal RNA gene chromatin

2008 ◽  
Vol 36 (4) ◽  
pp. 619-624 ◽  
Author(s):  
Joanna L. Birch ◽  
Joost C.B.M. Zomerdijk
Keyword(s):  
Ribosomal Rna ◽  
Ribosome Biogenesis ◽  
Rna Polymerase I ◽  
Rrna Genes ◽  
Rrna Gene ◽  
Pol I ◽  
And Function ◽  
Polymerase I ◽  
Cell Growth And Proliferation ◽  
Cellular Control

Transcription of the major ribosomal RNAs by Pol I (RNA polymerase I) is a key determinant of ribosome biogenesis, driving cell growth and proliferation in eukaryotes. Hundreds of copies of rRNA genes are present in each cell, and there is evidence that the cellular control of Pol I transcription involves adjustments to the number of rRNA genes actively engaged in transcription, as well as to the rate of transcription from each active gene. Chromatin structure is inextricably linked to rRNA gene activity, and the present review highlights recent advances in this area.

scholarly journals Matrix metalloproteinase-2 mediates ribosomal RNA transcription by cleaving nucleolar histones

2020 ◽  
Author(s):  
Mohammad A.M. Ali ◽  
Javier A. Garcia-Vilas ◽  
Christopher R. Cromwell ◽  
Basil P. Hubbard ◽  
Michael J. Hendzel ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Matrix Metalloproteinase ◽  
Ribosomal Rna ◽  
Ribosome Biogenesis ◽  
Histone H3 ◽  
Epigenetic Mechanism ◽  
Matrix Metalloproteinase 2 ◽  
Rrna Gene ◽  
Rrna Transcription ◽  
Genes Encoding

AbstractCell proliferation and survival require continuous ribosome biogenesis and protein synthesis. Genes encoding ribosomal RNA (rRNA) are physically located in a specialized substructure within the nucleus known as the nucleolus, which has a central role in the biogenesis of ribosomes. Matrix metalloproteinase-2 (MMP-2) was previously detected in the nucleus. However, its role there is elusive. Herein we report that MMP-2 resides within the nucleolus to regulate rRNA transcription. MMP-2 is enriched at the promoter region of rRNA gene repeats and its inhibition downregulates pre-rRNA transcription. The N-terminal tail of histone H3 is clipped by MMP-2 in the nucleolus and is associated with increased rRNA transcription. Knocking down/out MMP-2 or inhibiting its activity prevents histone H3 cleavage and reduces both rRNA transcription and cell proliferation. In addition to the known extracellular roles of MMP-2 in tumor growth, our data reveal an epigenetic mechanism whereby intranucleolar MMP-2 regulates cell proliferation through histone proteolysis and facilitation of rRNA transcription.

scholarly journals Aging and neurodegeneration are associated with increased mutations in single human neurons

2017 ◽  
Author(s):  
Michael A. Lodato ◽  
Rachel E. Rodin ◽  
Craig L. Bohrson ◽  
Michael E. Coulter ◽  
Alison R. Barton ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Genetic Disorders ◽  
Single Nucleotide Variants ◽  
Single Nucleotide ◽  
Age Related ◽  
Genome Wide ◽  
Normal Individuals ◽  
Human Neurons ◽  
Regional Specificity ◽  
Associated Conditions

SummaryIt has long been hypothesized that aging and neurodegeneration are associated with somatic mutation in neurons; however, methodological hurdles have prevented testing this hypothesis directly. We used single-cell whole-genome sequencing to perform genome-wide somatic single-nucleotide variant (sSNV) identification on DNA from 161 single neurons from the prefrontal cortex and hippocampus of fifteen normal individuals (aged 4 months to 82 years) as well as nine individuals affected by early-onset neurodegeneration due to genetic disorders of DNA repair (Cockayne syndrome and Xeroderma pigmentosum). sSNVs increased approximately linearly with age in both areas (with a higher rate in hippocampus) and were more abundant in neurodegenerative disease. The accumulation of somatic mutations with age—which we term genosenium—shows age-related, region-related, and disease-related molecular signatures, and may be important in other human age-associated conditions.One-Sentence SummarySomatic single-nucleotide variants accumulate in human neurons in aging with regional specificity and in progeroid diseases.

scholarly journals An RNA-binding switch drives ribosome biogenesis and tumorigenesis downstream of RAS oncogene

2021 ◽  
Author(s):  
Muhammad S Azman ◽  
Martin Dodel ◽  
Federica Capraro ◽  
Rupert Faraway ◽  
Maria Dermit ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ribosomal Rna ◽  
Ribosome Biogenesis ◽  
Rna Binding ◽  
Binding Activity ◽  
Ras Signaling ◽  
Cancer Cell Proliferation ◽  
Inhibit Tumor Growth ◽  
Oncogenic Ras

Oncogenic RAS signaling reprograms gene expression through both transcriptional and post-transcriptional mechanisms. While transcriptional regulation downstream of RAS is relatively well-characterized, how RAS post-transcriptionally modulates gene expression to promote malignancy is unclear. Using quantitative RNA Interactome Capture analysis, we reveal that oncogenic RAS signaling reshapes the RNA-bound proteomic landscape of cancer cells, with a network of nuclear proteins centered around Nucleolin displaying enhanced RNA-binding activity. We show that Nucleolin is phosphorylated downstream of RAS, which increases its binding to pre-ribosomal-RNA (rRNA), boosts rRNA production, and promotes ribosome biogenesis. This Nucleolin-dependent enhancement of ribosome biogenesis is crucial for RAS-induced cancer cell proliferation, and can be targeted therapeutically to inhibit tumor growth. Our results reveal that oncogenic RAS signaling drives ribosome biogenesis by regulating the RNA-binding activity of Nucleolin, and highlights the crucial role of this process in RAS-mediated tumorigenesis.

scholarly journals Che-1/AATF binds to RNA polymerase I machinery and sustains ribosomal RNA gene transcription

2020 ◽  
Vol 48 (11) ◽  
pp. 5891-5906 ◽  
Author(s):  
Cristina Sorino ◽  
Valeria Catena ◽  
Tiziana Bruno ◽  
Francesca De Nicola ◽  
Stefano Scalera ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Rna Polymerase ◽  
Ribosomal Rna ◽  
Ribosome Biogenesis ◽  
Cellular Proliferation ◽  
Rna Polymerase I ◽  
Rrna Synthesis ◽  
Rrna Gene ◽  
Response To Stress ◽  
Polymerase I

Abstract Originally identified as an RNA polymerase II interactor, Che-1/AATF (Che-1) has now been recognized as a multifunctional protein involved in cell-cycle regulation and cancer progression, as well as apoptosis inhibition and response to stress. This protein displays a peculiar nucleolar localization and it has recently been implicated in pre-rRNA processing and ribosome biogenesis. Here, we report the identification of a novel function of Che-1 in the regulation of ribosomal RNA (rRNA) synthesis, in both cancer and normal cells. We demonstrate that Che-1 interacts with RNA polymerase I and nucleolar upstream binding factor (UBF) and promotes RNA polymerase I-dependent transcription. Furthermore, this protein binds to the rRNA gene (rDNA) promoter and modulates its epigenetic state by contrasting the recruitment of HDAC1. Che-1 downregulation affects RNA polymerase I and UBF recruitment on rDNA and leads to reducing rDNA promoter activity and 47S pre-rRNA production. Interestingly, Che-1 depletion induces abnormal nucleolar morphology associated with re-distribution of nucleolar proteins. Finally, we show that upon DNA damage Che-1 re-localizes from rDNA to TP53 gene promoter to induce cell-cycle arrest. This previously uncharacterized function of Che-1 confirms the important role of this protein in the regulation of ribosome biogenesis, cellular proliferation and response to stress.

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