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PubMed1977

Interactions of murine leukemia virus core components: characterization of reverse transcriptase packaged in the absence of 70S genomic RNA.

Virions produced by cells in the presence of actinomycin D (Act D virions) contain reverse transcriptase but are deficient in 70S genomic RNA. To assess the role of genomic RNA in encapsidation of a functional reverse transcriptase and to study the interaction of the enzyme and its template in the cores of intact virions, the reverse transcriptase enzymes of normal and Act D virions were compared. The enzymes were indistinguishable by column chromatography, sedimentation velocity, or template/primer preferences. In addition, these enzymes showed equal sensitivity to inactivation by antibodies directed against Rauscher murine leukemia virus DNA polymerase. The enzymes from Act D and normal virions had similar thermal decay rates and were both protected against heat denaturation by natural and synthetic template/primers. By these criteria, the DNA polymerase molecules synthesized and assembled into virions in the absence of genomic RNA are identical to those packaged under normal conditions. Additional studies designed to measure protection of reverse transcriptase by genomic RNA were carried out by comparing the thermal lability of the enzyme in intact Act D and normal virions. The thermal decay rate of reverse transcriptase in Act D virions was identical to that in control virions. In contrast to the lability of the virion-associated enzyme, however, genomic RNA in control virions was stable to heat treatment.

AKR murine leukemia virus↗

PubMed1999

[Effect of inactivating various components of the signal pathways of the tumor suppressor p53 on genomic stability].

To evaluate the role of different p53-regulated signaling pathways in the control of genomic integrity, we studied the frequency of changes in chromosome number and structure of cells of the sublines of mouse primary embryonic fibroblasts with the "knocked-out" genes for proteins p53, p21WAF, pRb, and p19ARF. Protein p21WAF is transactivated by p53 and is responsible for the cell block in the G1 phase of the damaged cells; protein pRb is a target for p21WAF which controls the G1-S-phase transition; and p19ARF protein is responsible for p53 activation in cells with certain anomalies. Inactivation of either of the studied genes proved to increase significantly the frequency of changes in the karyotype. However, the resultant chromosome instability differed: the frequency of the chromosome breaks, both spontaneous and induced with ethylmethane sulfonate (EMS), was in cells with inactivated p53 and lowest in cells with inactivated pRb. These distinctions were not caused by a different effect of various gene inactivation on the cell cycle progression: in all sublines, the cell block in G1 was abolished and the checkpoint function in G2 remained normal. However, the induction of apoptosis in EMS-treated cells differed in the studied sublines. The lowest number of apoptotic nuclei were determined in p53-/- cultures, whereas the highest were in the Rb-/- cultures. It is apparent that the degree of genetic instability is determined by a combined effect of apoptosis and abnormal regulation of the cell-cycle checkpoints.

Animals↗

PubMed1998

Genome encyclopedias and their use for comparative analysis of Rhodobacter capsulatus strains.

This paper consists of two components: the use of gene encyclopedias in genomic studies and Rhodobacter capsulatus genome project. A survey of vectors used for encyclopedia construction includes a brief discussion of their relative advantages and limitations. Projects employing various methods of encyclopedia assembly including the comparison of restriction patterns, restriction maps, linking by hybridization, oligonucleotide fingerprinting, sequence tagged site (STS) fingerprinting and encyclopedias derived from genetic maps are listed and briefly described. The R. capsulatus SB 1003 genome project started with the construction of its cosmid encyclopedia, which comprises 192 cosmids covering the chromosome and the 134 kbp plasmid in strain SB 1003, with the exact map coordinates of each cosmid. In a pilot sequencing study, several cosmids were individually subcloned using the vector M13mp18 and merged into one 189 kbp contig. About 160 open reading frames (ORFs) identified by the CodonUse program were subjected to similarity searches. The biological functions of eighty ORFs could be assigned reliably using the WIT (what is there) genome investigation environment. Eighty percent of these recognizable ORFs were organized in functional clusters, which simplified assignment decisions and increased the strength of the predictions. A set of 26 genes for cobalamin biosynthesis, genes for polyhydroxyalkanoic acid metabolism, DNA replication and recombination, and DNA gyrase were among those identified. Recently, another 1.2 Mbp genome fragment of the Rhodobacter genome was sequenced using a slightly modified approach. These results together with some genome investigation tools, have been placed at our web site (http://capsulapedia.uchicago.edu). The sequence of R. capsulatus is expected to be completed by summer 1998. A project to construct a systematic set of deletion strains of R. capsulatus in order to assign functions to unknown ORFs has been started. Preliminary data demonstrate the extreme convenience of the unique gene transfer agent (GTA) system to perform such work.

Animals↗

PubMed2001

Features of the two gene pairs RD-SKI2W and DOM3Z-RP1 located between complement component genes factor B and C4 at the MHC class III region.

Located at the 30 kb genomic region between complement factor B and component C4 are four ubiquitously expressed genes RD, SKI2W, DOM3Z and RP1. Besides RP1, the protein products of the other three genes each has highly conserved homologues or related proteins in lower eukaryotes, contains leucine zipper motifs for protein interaction, and plays important roles related to RNA metabolism. RD is a subunit of the negative transcription elongation factor, critical for the regulation of gene expression. It has an RNA recognition motif and 24 copies of Arg-Asp (RD) repeats. Ski2w is a nucleolar and cytoplasmic protein that has a putative RNA helicase domain. Fusion proteins of human Ski2w expressed in insect cells and bacteria have ATPase activity. The cytoplasmic protein of human Ski2w is associated with the polysomes and probably the 40S subunit of ribosomes. Ski2w is probably involved in the regulation of translation and RNA turnover. Dom3z is a nuclear protein whose yeast homologue forms a complex with an exoribonuclease. RP1 (or STK19) is a Ser/Thr nuclear protein kinase. No homologues of RP1 in lower eukaryotes have been discovered. Six polymorphic residues are present in human Ski2w and two in Dom3z. The potential roles of Ski2w and Dom3z on the clearance of degraded nuclear and cytoplasmic RNA raised their possibilities as susceptibility genes of systemic lupus erythematosus that is a disease with flawed processes in the removal of apoptotic materials.

Amino Acid Sequence↗

PubMed2006

Autophagy and related processes in trypanosomatids: insights from genomic and bioinformatic analyses.

The targeting in eukaryotic cells of cellular components to the lysosome or vacuole for degradation is called autophagy. Not only cytoplasmic macromolecules and bulk cytoplasm are subject to this process; entire organelles such as peroxisomes can be degraded. Autophagy of peroxisomes is called pexophagy. Unpublished evidence suggests that the analogous processing of glycosomes in the protozoan kinetoplastids occurs. Taking advantage of the (near-) complete status of three trypanosomatid genomes, a census of components of autophagy and related processes has been undertaken in these organisms. Simple database searches were supplemented by more advanced analyses where necessary. At most, only half of the components characterized in yeasts are present in trypanosomatids suggesting an unexpectedly streamlined version of autophagy occurs in these organisms. The cytoplasm-to-vacuole targeting (Cvt) system for delivery of proteins to the vacuole seems entirely absent in trypanosomatids. The accuracy of the census is supported by the coordinated absence of functionally linked components such as the conjugation system involving ATG12, ATG5, ATG10 and ATG16 that acts at the step of vesicle expansion and completion. Overall, the results are consistent with a scenario of taxon-specific addition of components to a minimal core, a hypothesis that should be readily testable by further genomic surveys allied to laboratory experiments. A bioinformatics analysis of the trypanosomatidal proteins was carried out, highlighting the paucity of information available regarding their structures and enabling prioritization of targets for future structural biology work.

Animals↗

PubMed1996

Papillomavirus infections--a major cause of human cancers.

The papillomavirus family represents a remarkably heterogeneous group of viruses. At present, 77 distinct genotypes have been identified in humans and partial sequences have been obtained from more than 30 putative novel genotypes. Geographic differences in base composition of individual genotypes are generally small and suggest a low mutation rate and thus an ancient origin of today's prototypes. The relatively small size of the genome permitted an analysis of individual gene functions and of interactions of viral proteins with host cell components. Proliferating cells contain the viral genome in a latent form, large scale viral DNA replication, as well as translation and functional activity of late viral proteins, and viral particle assembly are restricted to differentiating layers of skin and mucosa. In humans papillomavirus infections cause a variety of benign proliferations: warts, epithelial cysts, intraepithelial neoplasias, anogenital, oro-laryngeal and -pharyngeal papillomas, keratoacanthomas and other types of hyperkeratoses. Their involvement in the etiology of some major human cancers is of particular interest: specific types (HPV 16, 18 and several others) have been identified as causative agents of at least 90% of cancers of the cervix and are also linked to more than 50% of other anogenital cancers. These HPV types are considered as 'high risk' infections. Their E6/E7 oncoproteins stimulate cell proliferation by activating cyclins E and A, and interfere with the functions of the cellular proteins RB and p53. The latter interaction appears to be responsible for their mutagenic and aneuploidizing activity as an underlying principle for the progression of these HPV-containing lesions and the role of high risk HPV types as solitary carcinogens. In non-transformed human keratinocytes transcription and function of viral oncoproteins is controlled by intercellular and intracellular signalling cascades, their interruption emerges as a precondition for immortalization and malignant growth. Recently, novel and known HPV types have also been identified in a high percentage of non-melanoma skin cancers (basal and squamous cell carcinomas). Similar to observations in patients with a rare hereditary condition, epidermodysplasia verruciformis, characterized by an extensive verrucosis and development of skin cancer, basal and squamous cell carcinomas develop preferentially in light-exposed sites. This could suggest an interaction between a physical carcinogen (UV-part of the sunlight) and a 'low risk' (non-mutagenic) papillomavirus infection. Reports on the presence of HPV infections in cancers of the oral cavity, the larynx, and the esophagus further emphasize the importance of this virus group as proven and suspected human carcinogens.

Cell Division↗

PubMed2000

Lineage-specific loss and divergence of functionally linked genes in eukaryotes.

By comparing 4,344 protein sequences from fission yeast Schizosaccharomyces pombe with all available eukaryotic sequences, we identified those genes that are conserved in S. pombe and nonfungal eukaryotes but are missing or highly diverged in the baker's yeast Saccharomyces cerevisiae. Since the radiation from the common ancestor with S. pombe, S. cerevisiae appears to have lost about 300 genes, and about 300 more genes have diverged by far beyond expectation. The most notable feature of the set of genes lost in S. cerevisiae is the coelimination of functionally connected groups of proteins, such as the signalosome and the spliceosome components. We predict similar coelimination of the components of the posttranscriptional gene-silencing system that includes the recently identified RNA-dependent RNA polymerase. Because one of the functions of posttranscriptional silencing appears to be "taming" of retrotransposons, the loss of this system in yeast could have triggered massive retrotransposition, resulting in elimination of introns and subsequent loss of spliceosome components that become dispensable. As the genome database grows, systematic analysis of coordinated gene loss may become a general approach for predicting new components of functional systems or even defining previously unknown functional complexes.

Biological Evolution↗

PubMed1988

Extent of the mouse t complex and its inversions shown by in situ hybridization.

Probes for loci situated near one end of the proximal (Tcp-1) and distal (Qa-2, 3) inversions of the mouse t complex have been hybridized to chromosomes of mice with and without t complexes and with morphologically distinguishable chromosome 17s. Both the probe for Tcp-1 and that for Qa-2, 3 hybridized to clearly different positions on t and non-t chromosomes, thus making visible the extent of the two inversions. The proximal inversion extends from roughly the junction of bands A1 and A2 to band A3, and the distal inversion from band A3 to band C. Thus, the whole t complex extends from the band A1-A2 junction to band C, and is therefore somewhat larger than previously thought, and occupies about 1.2% of the genome. A probe for complement component 3 (C3-1), genetically known to be several cM distal to the t complex, was found by in situ hybridization to lie in band E1. The proximal part of chromosome 17 is one of the best known parts of the mouse genome, at both the genetic and molecular levels. It may soon be possible to correlate the length of the t complex in terms of chromosomal distance with its physical length in megabases.

Animals↗

PubMed2000

Two-component systems in Pseudomonas aeruginosa: why so many?

Screening the Pseudomonas aeruginosa genome has led to the identification of the highest number of putative genes encoding two-component regulatory systems of all bacterial genomes sequenced to date (64 and 63 encoding response regulators and histidine kinases, respectively). Sixteen atypical kinases, among them 11 devoid of an Hpt domain, and three independent Hpt modules were retrieved. These data suggest that P. aeruginosa possesses complex control strategies with which to respond to environmental challenges.

Amino Acid Sequence↗

PubMed2005

Yeast genomics in the elucidation of endoplasmic reticulum (ER) quality control and associated protein degradation (ERQD).

The endoplasmic reticulum (ER) is the eukaryotic organelle where most secreted proteins enter the secretory pathway. They enter this organelle in an unfolded state and are folded by a highly active folding machinery to reach their native state. The ER contains an efficient protein quality control system, which recognizes malfolded and orphan proteins and targets them for elimination by a mechanism called ER-associated degradation (ERAD). Both processes are tightly linked, and they will be abbreviated as ERQD (ER quality control and associated degradation). Because ERQD is highly conserved from yeast to man, the easy amenability of yeast to genetic and molecular biological studies combined with the knowledge of its genome and proteome makes it a preferred organism to study such "housekeeping" functions of eukaryotic cells. New genomic and proteomic methods have led to new experimental concepts. Genome-wide screens using genomic deletion libraries led to the identification of genes involved in the processes in question. Using such a genome-wide approach, we devise a sensitive growth test for selection of yeast mutants defective in ERQD. A chimeric protein (CTL*) was generated consisting of the ER luminal, N-glycosylated CPY* protein fused to a transmembrane domain and cytoplasmic 3-isopropylmalate dehydrogenase, the Leu2 protein. In addition, the nonglycosylated ER-membrane-located ERQD substrate Sec61-2p was fused to Leu2p (Sec61-2-L*). Cells carrying a LEU2 deletion can only grow on medium lacking leucine when the chimeric protein CTL* or Sec61-2-L* is not degraded. Thus, only mutant cells defective in an ERQD component can grow. A genome-wide screen can be performed by transforming the CTL* or Sec61-2-L* coding DNA into the approximately 5000 individual deletion mutants of the EUROSCARF yeast library. Examples for new components required for ERQD found by this method are the mannose-6-phosphate receptor domain protein Yos9p and the ubiquitin domain proteins Dsk2p and Rad23p.

Endoplasmic Reticulum↗

PubMed2001

The molecular pathogenesis of prostate cancer: Implications for prostate cancer prevention.

Prostate cancer has become 1 of the most commonly diagnosed cancers in the United States and 1 of the leading causes of cancer death in North America and Western Europe. Survey studies of prostate tissues obtained at autopsy indicate that the development of life-threatening prostate cancer in the US likely occurs over decades. Insights from epidemiologic studies implicate environmental factors, principally dietary components, as major risk factors for prostate cancer development. An accumulating body of basic research data suggests that normal and neoplastic prostate cells may be subjected to a relentless barrage of genome-damaging stresses, and that dietary components and male sex steroids might modulate the level of genome threatening insults. Finally, over the past 5 years, analyses of somatic genome alterations in prostatic carcinoma cells have revealed that somatic inactivation of GSTP1, encoding the carcinogen-detoxification enzyme glutathione S-transferase pi, may serve as an initiating genome lesion for prostatic carcinogenesis. These diverse observations can be integrated into a transcendent mechanistic hypothesis for the pathogenesis of prostate cancer: normal prostate cells acquiring somatic GSTP1 defects may suffer chronic genome damage, influenced by dietary practices, that promote neoplastic transformation, while prostatic carcinoma cells, which characteristically contain defective GSTP1 alleles, remain susceptible to further genome-damaging stresses that promote malignant cancer progression. This hypothesized critical role for GSTP1 inactivation in the earliest steps of prostatic carcinogenesis provides several attractive opportunities for prostate cancer prevention strategies, including (1) restoration of GSTP1 function, (2) compensation for inadequate GSTP1 activity (via use of therapeutic inducers of other glutathione S-transferases (GST), and (3) abrogation or attenuation of genome-damaging stresses.

Atrophy↗

PubMed2004

Major quantitative trait locus for eosinophil count is located on chromosome 2q.

BACKGROUND: Eosinophils are granulocytic white blood cells implicated in asthma and atopic disease. The degree of eosinophilia in the blood of patients with asthma correlates with the severity of asthmatic symptoms. Quantitative trait loci (QTL) linkage analysis of eosinophil count may be a more powerful strategy of mapping genes involved in asthma than linkage analysis using affected relative pairs. OBJECTIVE: To identify QTLs responsible for variation in eosinophil count in adolescent twins. METHODS: We measured eosinophil count longitudinally in 738 pairs of twins at 12, 14, and 16 years of age. We typed 757 highly polymorphic microsatellite markers at an average spacing of approximately 5 centimorgans across the genome. We then used multipoint variance components linkage analysis to test for linkage between marker loci and eosinophil concentrations at each age across the genome. RESULTS: We found highly significant linkage on chromosome 2q33 in 12-year-old twins (logarithm of the odds=4.6; P=.000002) and suggestive evidence of linkage in the same region in 14-year-olds (logarithm of the odds=1.0; P=.016). We also found suggestive evidence of linkage at other areas of the genome, including regions on chromosomes 2, 3, 4, 8, 9, 11, 12, 17, 20, and 22. CONCLUSION: A QTL for eosinophil count is present on chromosome 2q33. This QTL might represent a gene involved in asthma pathophysiology.

Adolescent↗

PubMed2005

ProGenExpress: visualization of quantitative data on prokaryotic genomes.

BACKGROUND: The integration of genomic information with quantitative experimental data is a key component of systems biology. An increasing number of microbial genomes are being sequenced, leading to an increasing amount of data from post-genomics technologies. The genomes of prokaryotes contain many structures of interest, such as operons, pathogenicity islands and prophage sequences, whose behaviour is of interest during infection and disease. There is a need for simple and novel tools to display and analyse data from these integrated datasets, and we have developed ProGenExpress as a tool for visualising arbitrarily complex numerical data in the context of prokaryotic genomes. RESULTS: Here we describe ProGenExpress, an R package that allows researchers to easily and quickly visualize quantitative measurements, such as those produced by microarray experiments, in the context of the genome organization of sequenced prokaryotes. Data from microarrays, proteomics or other whole-genome technologies can be accurately displayed on the genome. ProGenExpress can also search for novel regions of interest that consist of groups of adjacent genes that show similar patterns across the experimental data set. We demonstrate ProGenExpress with microarray data from a time-course experiment involving Salmonella typhimurium. CONCLUSION: ProGenExpress can be used to visualize quantitative data from complex experiments in the context of the genome of sequenced prokaryotes, and to find novel regions of interest.

Computational Biology↗

PubMed1993

A transcription map of the chloroplast genome from rice (Oryza sativa).

The complete nucleotide sequence (134,525 bp) of the chloroplast genome from rice (Oryza sativa L.) contains four rRNA genes, 30 tRNA genes, and over 100 genes that encode proteins. However, expression of only a few of these genes, namely psbA, rbcL, and atpB/E, has been detected. We constructed the complete transcription map of rice chloroplast DNA by Northern hybridization of total RNA from rice seedlings, using subclones from a clone bank of rice chloroplast DNA as probes. Approximately 90% of the chloroplast genome was transcribed, as detected by a non-radioactive hybridization system. Most of the genes on the chloroplast DNA are organized as clusters and are co-transcribed as long primary transcripts. We identified 16 polycistronic transcripts from the rice chloroplast genome. Furthermore, the genes for components of photosystems I and II, the gene for the large subunit of RuBisCO, the genes for ATPase, the genes for components of the cytochrome complex, and the rRNA genes were expressed at the highest levels.

ATP Synthetase Complexes↗

PubMed1990

The nucleotide sequence of the equine herpesvirus 4 gC gene homologue.

The genomic position of an equine herpesvirus 4 (EHV-4) gene homologue of the herpes simplex virus 1 (HSV-1) gC gene was determined by Southern analysis and DNA sequencing. The gene lies within a 2-kbp Bg/II-EcoRI fragment mapping between 0.15 and 0.17 within the long unique component of the EHV-4 genome and is transcribed from right to left. Putative promoter elements were identified upstream of the 1455-bp open reading frame which encodes a 485-amino-acid protein of unglycosylated molecular weight 52,513. Computer-assisted analysis of the primary sequence predicts the protein possesses a domain structure characteristic of a type 1 integral membrane glycoprotein. Four domains were distinguished--(i) an N-terminal signal sequence, (ii) a large extracellular domain containing 11 putative N-linked glycosylation sites, (iii) a hydrophobic transmembrane domain, and (iv) a C-terminal charged domain. Comparison of the predicted amino acid sequence to that of other herpesvirus glycoproteins indicated identities of between 22 and 29% with HSV-1 gC, HSV-2 gC, VZV gpV, PRV gIII, BHV-1 gIII, and MDV A antigen and of 79% with EHV-1 gp13. A gene with no apparent homologue in HSV-1 or VZV maps immediately downstream of the EHV-4 gC gene homologue.

Amino Acid Sequence↗

PubMed2024

The effect of fampridine on working memory: a randomized controlled trial based on a genome-guided repurposing approach.

Working memory (WM), a key component of cognitive functions, is often impaired in psychiatric disorders such as schizophrenia. Through a genome-guided drug repurposing approach, we identified fampridine, a potassium channel blocker used to improve walking in multiple sclerosis, as a candidate for modulating WM. In a subsequent double-blind, randomized, placebo-controlled, crossover trial in 43 healthy young adults (ClinicalTrials.gov, NCT04652557), we assessed fampridine's impact on WM (3-back d-prime, primary outcome) after 3.5 days of repeated administration (10 mg twice daily). Independently of baseline cognitive performance, no significant main effect was observed (Wilcoxon P = 0.87, r = 0.026). However, lower baseline performance was associated with higher working memory performance after repeated intake of fampridine compared to placebo (rs = -0.37, P = 0.014, n = 43). Additionally, repeated intake of fampridine lowered resting motor threshold (F(1,37) = 5.31, P = 0.027, R2β = 0.01), the non-behavioral secondary outcome, indicating increased cortical excitability linked to cognitive function. Fampridine's capacity to enhance WM in low-performing individuals and to increase brain excitability points to its potential value for treating WM deficits.

Adult↗

PubMed2006

Applying mobile genetic elements for genome analysis and evolution.

Transposable elements (TEs) are ubiquitous components of all living organisms, and in the course of their coexistence with their respective host genomes, these parasitc DNAs have played important roles in the evolution of complex genetic networks. The interaction between mobile DNAs and their host genomes are quite diverse, ranging from modifications of gene structure and regulation to alterations in general genome architecture. Thus during evolutionary time these elements can be regarded as natural molecular tools in shaping the organization, structure, and function of eukaryotic genes and genomes. Based on their intrinsic properties and features, mobile DNAs are widely applied at present as a technical "toolbox," essential for studying a diverse spectrum of biological questions. In this review, we aim to summarize both the evolutionary impact of TEs on genome evolution and their valuable and diverse methodological applications as molecular tools.

Animals↗

PubMed2000

New components of a system for phosphate accumulation and polyphosphate metabolism in Saccharomyces cerevisiae revealed by genomic expression analysis.

The PHO regulatory pathway is involved in the acquisition of phosphate (P(i)) in the yeast Saccharomyces cerevisiae. When extracellular P(i) concentrations are low, several genes are transcriptionally induced by this pathway, which includes the Pho4 transcriptional activator, the Pho80-Pho85 cyclin-CDK pair, and the Pho81 CDK inhibitor. In an attempt to identify all the components regulated by this system, a whole-genome DNA microarray analysis was employed, and 22 PHO-regulated genes were identified. The promoter regions of 21 of these genes contained at least one copy of a sequence that matched the Pho4 recognition site. Eight of these genes, PHM1-PHM8, had no previously defined function in phosphate metabolism. The amino acid sequences of PHM1 (YFL004w), PHM2 (YPL019c), PHM3 (YJL012c), and PHM4 (YER072w) are 32-56% identical. The phm3 and phm4 single mutants and the phm1 phm2 double mutant were each severely deficient in accumulation of inorganic polyphosphate (polyP) and P(i). The phenotype of the phm5 mutant suggests that PHM5 (YDR452w) is essential for normal catabolism of polyP in the yeast vacuole. Taken together, the results reveal important new features of a genetic system that plays a critical role in P(i) acquisition and polyP metabolism in yeast.

Acid Anhydride Hydrolases↗