scholarly journals Different genetic mechanisms mediate spontaneous versus UVR-induced malignant melanoma

2018 ◽  
Author(s):  
Blake Ferguson ◽  
Herlina Y. Handoko ◽  
Pamela Mukhopadhyay ◽  
Arash Chitsazan ◽  
Lois Balmer ◽  
...  
Keyword(s):  
Ribosome Biogenesis ◽  
Inflammatory Cell ◽  
Ribosomal Subunit ◽  
Rapid Onset ◽  
Mouse Strains ◽  
Subunit Gene ◽  
Genetic Mechanisms ◽  
Trait Locus ◽  
Defective Dna Repair ◽  
Transgenic Progeny

AbstractGenetic variation conferring resistance and susceptibility to carcinogen-induced tumorigenesis is frequently studied in mice. We have now turned this to melanoma using the collaborative cross (CC), a resource of mouse strains designed to discover genes for complex diseases. We studied melanoma-prone transgenic progeny across seventy CC genetic backgrounds. We mapped a strong quantitative trait locus for rapid onset spontaneous melanoma onset toPrkdc, a gene involved in detection and repair of DNA damage. In contrast, rapid onset UVR-induced melanoma was linked to the ribosomal subunit geneRrp15. Ribosome biogenesis was upregulated in skin shortly after UVR exposure, Mechanistically, variation in the “usual suspects” by which UVR may exacerbate melanoma, defective DNA repair, melanocyte proliferation, or inflammatory cell infiltration, did not explain melanoma susceptibility or resistance across the CC. Instead, events occurring soon after exposure, such as dysregulation of ribosome function, which alters many aspects of cellular metabolism, may be important.

scholarly journals Different genetic mechanisms mediate spontaneous versus UVR-induced malignant melanoma

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Blake Ferguson ◽  
Herlina Y Handoko ◽  
Pamela Mukhopadhyay ◽  
Arash Chitsazan ◽  
Lois Balmer ◽  
...  
Keyword(s):  
Ribosome Biogenesis ◽  
Inflammatory Cell ◽  
Ribosomal Subunit ◽  
Rapid Onset ◽  
Mouse Strains ◽  
Subunit Gene ◽  
Genetic Mechanisms ◽  
Trait Locus ◽  
Defective Dna Repair ◽  
Transgenic Progeny

Genetic variation conferring resistance and susceptibility to carcinogen-induced tumorigenesis is frequently studied in mice. We have now turned this idea to melanoma using the collaborative cross (CC), a resource of mouse strains designed to discover genes for complex diseases. We studied melanoma-prone transgenic progeny across seventy CC genetic backgrounds. We mapped a strong quantitative trait locus for rapid onset spontaneous melanoma onset to Prkdc, a gene involved in detection and repair of DNA damage. In contrast, rapid onset UVR-induced melanoma was linked to the ribosomal subunit gene Rrp15. Ribosome biogenesis was upregulated in skin shortly after UVR exposure. Mechanistically, variation in the ‘usual suspects’ by which UVR may exacerbate melanoma, defective DNA repair, melanocyte proliferation, or inflammatory cell infiltration, did not explain melanoma susceptibility or resistance across the CC. Instead, events occurring soon after exposure, such as dysregulation of ribosome function, which alters many aspects of cellular metabolism, may be important.

scholarly journals Structural basis of GTPase-mediated mitochondrial ribosome biogenesis and recycling

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hauke S. Hillen ◽  
Elena Lavdovskaia ◽  
Franziska Nadler ◽  
Elisa Hanitsch ◽  
Andreas Linden ◽  
...  
Keyword(s):  
Ribosomal Proteins ◽  
Ribosome Biogenesis ◽  
Ribosomal Subunit ◽  
Structural Basis ◽  
Peptidyl Transferase ◽  
Mitochondrial Ribosomes ◽  
Mitochondrial Ribosome ◽  
In Vitro Reconstitution

AbstractRibosome biogenesis requires auxiliary factors to promote folding and assembly of ribosomal proteins and RNA. Particularly, maturation of the peptidyl transferase center (PTC) is mediated by conserved GTPases, but the molecular basis is poorly understood. Here, we define the mechanism of GTPase-driven maturation of the human mitochondrial large ribosomal subunit (mtLSU) using endogenous complex purification, in vitro reconstitution and cryo-EM. Structures of transient native mtLSU assembly intermediates that accumulate in GTPBP6-deficient cells reveal how the biogenesis factors GTPBP5, MTERF4 and NSUN4 facilitate PTC folding. Addition of recombinant GTPBP6 reconstitutes late mtLSU biogenesis in vitro and shows that GTPBP6 triggers a molecular switch and progression to a near-mature PTC state. Additionally, cryo-EM analysis of GTPBP6-treated mature mitochondrial ribosomes reveals the structural basis for the dual-role of GTPBP6 in ribosome biogenesis and recycling. Together, these results provide a framework for understanding step-wise PTC folding as a critical conserved quality control checkpoint.

scholarly journals The Putative RNA Helicase Dbp6p Functionally Interacts With Rpl3p, Nop8p and the Novel trans-acting Factor Rsa3p During Biogenesis of 60S Ribosomal Subunits in Saccharomyces cerevisiae

Genetics ◽  
2004 ◽  
Vol 166 (4) ◽  
pp. 1687-1699
Author(s):  
Jesús de la Cruz ◽  
Thierry Lacombe ◽  
Olivier Deloche ◽  
Patrick Linder ◽  
Dieter Kressler
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Ribosome Biogenesis ◽  
Null Allele ◽  
Ribosomal Subunit ◽  
Interaction Network ◽  
The Novel ◽  
Rna Helicases ◽  
Ribosomal Subunits ◽  
Synthetic Lethal ◽  
Synthetically Lethal

Abstract Ribosome biogenesis requires at least 18 putative ATP-dependent RNA helicases in Saccharomyces cerevisiae. To explore the functional environment of one of these putative RNA helicases, Dbp6p, we have performed a synthetic lethal screen with dbp6 alleles. We have previously characterized the nonessential Rsa1p, whose null allele is synthetically lethal with dbp6 alleles. Here, we report on the characterization of the four remaining synthetic lethal mutants, which reveals that Dbp6p also functionally interacts with Rpl3p, Nop8p, and the so-far-uncharacterized Rsa3p (ribosome assembly 3). The nonessential Rsa3p is a predominantly nucleolar protein required for optimal biogenesis of 60S ribosomal subunits. Both Dbp6p and Rsa3p are associated with complexes that most likely correspond to early pre-60S ribosomal particles. Moreover, Rsa3p is co-immunoprecipitated with protA-tagged Dbp6p under low salt conditions. In addition, we have established a synthetic interaction network among factors involved in different aspects of 60S-ribosomal-subunit biogenesis. This extensive genetic analysis reveals that the rsa3 null mutant displays some specificity by being synthetically lethal with dbp6 alleles and by showing some synthetic enhancement with the nop8-101 and the rsa1 null allele.

scholarly journals Genetic Mechanisms Underlying Apimaysin and Maysin Synthesis and Corn Earworm Antibiosis in Maize (Zea mays L.)

Genetics ◽  
1998 ◽  
Vol 149 (4) ◽  
pp. 1997-2006
Author(s):  
E A Lee ◽  
P F Byrne ◽  
M D McMullen ◽  
M E Snook ◽  
B R Wiseman ◽  
...  
Keyword(s):  
Helicoverpa Zea ◽  
Larval Growth ◽  
Corn Earworm ◽  
Phenotypic Variance ◽  
Significant Qtls ◽  
F2 Population ◽  
Genetic Mechanisms ◽  
Trait Locus ◽  
Maize Silks ◽  
Related Compounds

Abstract C-glycosyl flavones in maize silks confer resistance (i.e., antibiosis) to corn earworm (Helicoverpa zea [Boddie]) larvae and are distinguished by their B-ring substitutions, with maysin and apimaysin being the di- and monohydroxy B-ring forms, respectively. Herein, we examine the genetic mechanisms underlying the synthesis of maysin and apimaysin and the corresponding effects on corn earworm larval growth. Using an F2 population, we found a quantitative trait locus (QTL), rem1, which accounted for 55.3% of the phenotypic variance for maysin, and a QTL, pr1, which explained 64.7% of the phenotypic variance for apimaysin. The maysin QTL did not affect apimaysin synthesis, and the apimaysin QTL did not affect maysin synthesis, suggesting that the synthesis of these closely related compounds occurs independently. The two QTLs, rem1 and pr1, were involved in a significant epistatic interaction for total flavones, suggesting that a ceiling exists governing the total possible amount of C-glycosyl flavone. The maysin and apimaysin QTLs were significant QTLs for corn earworm antibiosis, accounting for 14.1% (rem1) and 14.7% (pr1) of the phenotypic variation. An additional QTL, represented by umc85 on the short arm of chromosome 6, affected antibiosis (R2 = 15.2%), but did not affect the synthesis of the C-glycosyl flavones.

scholarly journals Bop1 Is a Mouse WD40 Repeat Nucleolar Protein Involved in 28S and 5.8S rRNA Processing and 60S Ribosome Biogenesis

2000 ◽  
Vol 20 (15) ◽  
pp. 5516-5528 ◽  
Author(s):  
Žaklina Strezoska ◽  
Dimitri G. Pestov ◽  
Lester F. Lau
Keyword(s):  
Ribosome Biogenesis ◽  
Ribosomal Subunit ◽  
Weight Fraction ◽  
Rnase A ◽  
Mutant Form ◽  
Rrna Processing ◽  
Ribonucleoprotein Complexes ◽  
Nuclear Extracts ◽  
Mouse Tissues ◽  
Mouse Cells

ABSTRACT We have identified and characterized a novel mouse protein, Bop1, which contains WD40 repeats and is highly conserved through evolution. bop1 is ubiquitously expressed in all mouse tissues examined and is upregulated during mid-G1 in serum-stimulated fibroblasts. Immunofluorescence analysis shows that Bop1 is localized predominantly to the nucleolus. In sucrose density gradients, Bop1 from nuclear extracts cosediments with the 50S-80S ribonucleoprotein particles that contain the 32S rRNA precursor. RNase A treatment disrupts these particles and releases Bop1 into a low-molecular-weight fraction. A mutant form of Bop1, Bop1Δ, which lacks 231 amino acids in the N- terminus, is colocalized with wild-type Bop1 in the nucleolus and in ribonucleoprotein complexes. Expression of Bop1Δ leads to cell growth arrest in the G1phase and results in a specific inhibition of the synthesis of the 28S and 5.8S rRNAs without affecting 18S rRNA formation. Pulse-chase analyses show that Bop1Δ expression results in a partial inhibition in the conversion of the 36S to the 32S pre-rRNA and a complete inhibition of the processing of the 32S pre-rRNA to form the mature 28S and 5.8S rRNAs. Concomitant with these defects in rRNA processing, expression of Bop1Δ in mouse cells leads to a deficit in the cytosolic 60S ribosomal subunits. These studies thus identify Bop1 as a novel, nonribosomal mammalian protein that plays a key role in the formation of the mature 28S and 5.8S rRNAs and in the biogenesis of the 60S ribosomal subunit.

scholarly journals High Mortality with Severe Dystrophic Cardiac Calcinosis in C3H/OUJ Mice Fed High Fat Purified Diets

1988 ◽  
Vol 25 (2) ◽  
pp. 113-118 ◽  
Author(s):  
J. I. Everitt ◽  
L. M. Olson ◽  
J. B. Mangum ◽  
W. J. Visek
Keyword(s):  
High Fat Diet ◽  
Inflammatory Cell ◽  
Mouse Strains ◽  
Cardiovascular Collapse ◽  
Pathological Changes ◽  
High Fat ◽  
Low Fat Diet ◽  
Myocardial Degeneration ◽  
Lactating Females ◽  
Hydrogenated Soybean Oil

Severe degenerative myocardial disease occurred in female C3H/OUJ mice fed purified diets for 36 weeks; the diet contained 5% or 20% fat as non-hydrogenated soybean oil. Deaths of lactating females of this group (17/35 high fat diet and 7/35 low fat diet animals) were due to sudden cardiovascular collapse. Cardiomegaly with marked atrial and ventricular myocardial mineralization was seen at necropsy. Histologically. the random, myopathic foci were characterized by severe myocardial degeneration, mineralization, and fibrosis. Mural thrombosis, pulmonary arteriosclerosis, and mild myocardial inflammatory cell infiltrates were also present. Pathological changes were similar to those of dystrophic cardiac calcinosis, an incidental necropsy finding in certain mouse strains.

scholarly journals A susceptibility locus on chromosome 13 profoundly impacts the stability of genomic imprinting in mouse pluripotent stem cells

2020 ◽  
Author(s):  
Emily Swanzey ◽  
Thomas F. McNamara ◽  
Effie Apostolou ◽  
Mamta Tahiliani ◽  
Matthias Stadtfeld
Keyword(s):  
Culture Conditions ◽  
Mouse Strains ◽  
Genetic Determinant ◽  
Pluripotent Cells ◽  
Developmental Potential ◽  
Chromosome 13 ◽  
Non Invasive ◽  
Epigenetic Instability ◽  
Trait Locus ◽  
The Stability

SummaryCultured pluripotent cells accumulate detrimental epigenetic alterations, including DNA methylation changes at imprinted genes known as loss-of-imprinting (LOI). Despite the substantial biomedical relevance of this phenomenon, the molecular cause of this epigenetic instability in pluripotent cells remains unknown. While the occurrence of LOI is generally considered a stochastic phenomenon, here we document a strong genetic determinant that segregates mouse pluripotent cells into epigenetically stable and unstable cell lines. Unstable lines exhibit hypermethylation at Dlk1-Dio3 and select other imprinted loci, which is associated with impaired developmental potential. Stimulation of demethylases by ascorbic acid prevents LOI and can preserve developmental potential. Susceptibility to LOI greatly differs between commonly used mouse strains, which we utilize to map a causal region on chromosome 13 with Quantitative Trait Locus (QTL) analysis. Our observations identify a strong genetic determinant of locus-specific epigenetic abnormalities in pluripotent cells and provide a non-invasive way to suppress them. This highlights the importance of considering genetics in conjunction with culture conditions for assuring the quality of pluripotent cells for biomedical applications.

scholarly journals Quantitative trait loci associated with susceptibility to therapy-related acute murine promyelocytic leukemia in hCG-PML/RARA transgenic mice

Blood ◽  
2008 ◽  
Vol 112 (4) ◽  
pp. 1434-1442 ◽  
Author(s):  
Ryan K. Funk ◽  
Taylor J. Maxwell ◽  
Masayo Izumi ◽  
Deepa Edwin ◽  
Friederike Kreisel ◽  
...  
Keyword(s):  
Quantitative Trait ◽  
Complex Trait ◽  
Myelogenous Leukemia ◽  
Mouse Strains ◽  
Spleen Weight ◽  
Nucleotide Polymorphisms ◽  
Treatment Regimens ◽  
Multiple Loci ◽  
Acute Myelogenous ◽  
Trait Locus

Abstract Therapy-related acute myelogenous leukemia (t-AML) is an important late adverse effect of alkylator chemotherapy. Susceptibility to t-AML has a genetic component, yet specific genetic variants that influence susceptibility are poorly understood. We analyzed an F2 intercross (n = 282 mice) between mouse strains resistant or susceptible to t-AML induced by the alkylator ethyl-N-nitrosourea (ENU) to identify genes that regulate t-AML susceptibility. Each mouse carried the hCG-PML/RARA transgene, a well-characterized initiator of myeloid leukemia. In the absence of ENU treatment, transgenic F2 mice developed leukemia with higher incidence (79.4% vs 12.5%) and at earlier time points (108 days vs 234 days) than mice in the resistant background. ENU treatment of F2 mice further increased incidence (90.4%) and shortened median survival (171 vs 254 days). We genotyped F2 mice at 384 informative single nucleotide polymorphisms across the genome and performed quantitative trait locus (QTL) analysis. Thirteen QTLs significantly associated with leukemia-free survival, spleen weight, or white blood cell count were identified on 8 chromosomes. These results suggest that susceptibility to ENU-induced leukemia in mice is a complex trait governed by genes at multiple loci. Improved understanding of genetic risk factors should lead to tailored treatment regimens that reduce risk for patients predisposed to t-AML.

scholarly journals Arabidopsis small nucleolar RNA monitors the efficient pre-rRNA processing during ribosome biogenesis

2016 ◽  
Vol 113 (42) ◽  
pp. 11967-11972 ◽  
Author(s):  
Pan Zhu ◽  
Yuqiu Wang ◽  
Nanxun Qin ◽  
Feng Wang ◽  
Jia Wang ◽  
...  
Keyword(s):  
Ribosome Biogenesis ◽  
Higher Plants ◽  
Ribosomal Subunit ◽  
Rrna Processing ◽  
Developmental Defects ◽  
Protein Mutants ◽  
5.8S Rrna ◽  
Important Regulator ◽  
Nucleolar Rna

Ribosome production in eukaryotes requires the complex and precise coordination of several hundred assembly factors, including many small nucleolar RNAs (snoRNAs). However, at present, the distinct role of key snoRNAs in ribosome biogenesis remains poorly understood in higher plants. Here we report that a previously uncharacterized C (RUGAUGA)/D (CUGA) type snoRNA, HIDDEN TREASURE 2 (HID2), acts as an important regulator of ribosome biogenesis through a snoRNA–rRNA interaction. Nucleolus-localized HID2 is actively expressed in Arabidopsis proliferative tissues, whereas defects in HID2 cause a series of developmental defects reminiscent of ribosomal protein mutants. HID2 associates with the precursor 45S rRNA and promotes the efficiency and accuracy of pre-rRNA processing. Intriguingly, disrupting HID2 in Arabidopsis appears to impair the integrity of 27SB, a key pre-rRNA intermediate that generates 25S and 5.8S rRNA and is known to be vital for the synthesis of the 60S large ribosomal subunit and also produces an imbalanced ribosome profile. Finally, we demonstrate that the antisense-box of HID2 is both functionally essential and highly conserved in eukaryotes. Overall, our study reveals the vital and possibly conserved role of a snoRNA in monitoring the efficiency of pre-rRNA processing during ribosome biogenesis.

scholarly journals Obesity in Childhood and Adolescence, Genetic Factors

PRILOZI ◽  
2017 ◽  
Vol 38 (3) ◽  
pp. 121-133 ◽  
Author(s):  
Marko Kostovski ◽  
Velibor Tasic ◽  
Nevena Laban ◽  
Momir Polenakovic ◽  
Dragan Danilovski ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Rapid Onset ◽  
Modern World ◽  
Childhood And Adolescence ◽  
Monogenic Obesity ◽  
Wagr Syndrome ◽  
The Family ◽  
Genetic Mechanisms ◽  
Childhood And Adolescent Obesity ◽  
Carbohydrate Intolerance

AbstractObesity and excess weight are a pandemic phenomenon in the modern world. Childhood and adolescent obesity often ends up in obesity in adults. The costs of obesity and its consequences are staggering for any society, crippling for countries in development. Childhood obesity is also widespread in Macedonia. Metabolic syndrome, dyslipidemia and carbohydrate intolerance are found in significant numbers. Parents and grandparents are often obese. Some of the children are either dysmorphic, or slightly retarded. We have already described patients with Prader-Willi syndrome, Bardet-Biedl syndrome or WAGR syndrome. A genetic screening for mutations in monogenic obesity in children with early, rapid-onset or severe obesity, severe hyperphagia, hypogonadism, intestinal dysfunction, hypopigmentation of hair and skin, postprandial hypoglycaemia, diabetes insipidus, abnormal leptin level and coexistence of lean and obese siblings in the family discovers many genetic forms of obesity. There are about 30 monogenic forms of obesity. In addition, obesity is different in ethnic groups, and the types of monogenic obesity differ. In brief, an increasing number of genes and genetic mechanisms in children continue to be discovered. This sheds new light on the molecular mechanisms of obesity and potentially gives a target for new forms of treatment.

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