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PubMed1987

Independent 5' and 3'-end determination of multiple dihydrofolate reductase transcripts.

Multiple dihydrofolate reductase (dhfr) mRNAs, differing substantially in abundance, are produced as a result of the utilization of multiple transcription initiation sites and multiple polyadenylation sites. We have shown that dhfr mRNAs initiating from an upstream promoter region utilize the same collection of six polyadenylation sites and generate multiple dhfr mRNAs at the same relative abundance as do the mRNAs initiating from the major transcription promoter region. These results indicate that the 5' and 3' ends of dhfr mRNAs are independently determined. We show that the relative abundance of steady-state dhfr mRNAs was the same in nuclear and cytoplasmic RNA fractions. This finding makes it unlikely that differences in mRNA stability account for differences in the relative abundance of the multiple dhfr mRNAs in the cytoplasm. Our analysis of the dhfr promoter region revealed the existence of stable cytoplasmic polyadenylated transcripts complementary to the first 300 nucleotides of the dhfr transcripts initiating from the upstream promoter region. Therefore, the dhfr locus hosts two divergent and partially overlapping genes which share the same promoter region.

Animals↗
PubMedDate not supplied

Characterization of LlaCI, a new restriction-modification system from Lactococcus lactis subsp. cremoris W15.

The genes encoding the restriction-modification (R/M) system LlaCI have been found on the naturally occurring 7.0 kb plasmid pAW153 in L. lactis subsp. cremoris W15. The R/M system was isolated on a chloramphenicol resistant derivative of the wild type plasmid (pAW153cat). Plasmid pAW153cat and a 2.4 kb HincII-SphI fragment cloned into a high- and a low-copy vector conferred decreased sensitivity in L. lactis LM2301 and L. lactis SMQ86 against small isometric-headed phages of the 936 or P335 species, respectively. Increased plasmid copy number enhanced the level of phage restriction. Sequencing the 2.4 kb HincII-SphI fragment revealed two open reading frames arranged convergently with a 94 bp separation. IlaCIM showed 66% identity to hindIIIM, and IlaCIR showed 45% identity to hindIIIR. The organization of the LlaCI operon differs from the HindIII operon, where the endonuclease and methylase genes overlap and are transcribed in the same direction. The LlaCI methylase is predicted to be 296 amino acids long, with 63% identity to the HindIII methylase, while the LlaCI endonuclease is predicted to consist of 324 or 332 amino acids, depending on the position of the start codon. It shows 24% identity to the HindIII endonuclease.

Amino Acid Sequence↗
PubMed2004

Influence of mutations in the hepatitis B virus genome on virus replication and drug resistance--implications for novel antiviral strategies.

Persistent infection with the hepatitis B virus (HBV) represents a major health problem worldwide with over 350 million patients at risk of developing liver cirrhosis or hepatocellular carcinoma. HBV is a small, partially double-stranded DNA virus with four overlapping genes and a unique life cycle, creating an intracellular pool of covalently closed circular DNA molecules for persistence and an RNA template for replication via reverse transcription. Mutations occur frequently, and particular selection pressures, both endogenous (host immune clearance) and exogenous (vaccines and antivirals), readily select escape mutants. For example, HBeAg-negative chronic HBV infection with either basal core promoter or precore mutations is predominant in many parts of the world. Therapy of HBV infection with the nucleoside analogue lamivudine frequently leads to the selection of drug-resistant strains with polymerase mutations. Treatment options for chronic HBV infection include at present either interferon-alpha or the oral nucleos(t)ide analogues lamivudine or adefovir. However, these drugs have drawbacks, including possible serious side effects and low response rates in HBeAg-negative patients in the case of interferon or recurrence of viremia after cessation of therapy and development of escape mutants after a long period of treatment with nucleoside inhibitors. Recent advances of in vitro and in vivo models allow to study new antiviral strategies, including novel nucleoside analogues, nucleocapsid inhibitors or small interfering RNA. This review summarises the impact of clinically relevant mutations in the HBV genome on viral replication and drug sensitivity, the current status of therapy and promising future perspectives on novel drug regimens.

Animals↗
PubMed2002

[p16INK4a exon 1 alpha knockout in mouse embryonic stem cells].

INK4a/ARF locus distinguishes itself by its unusual structure and function. It contains 2 overlapping genes with exons 1 alpha, 2 and 3 encoding p16INK4a and exons 1 beta, 2 and 3 encoding p19ARF. Mice with their exons 2 and 3 of the INK4a/ARF knocked out are viable and fertile but develop spontaneous tumors at an early age and highly sensitive to carcinogenic treatment. However, mice with their exon 1 beta knocked out, without interference the expression of p16INK4a, show almost the same phenotype as those with their exons 2 and 3 knocked out. This raises a question of whether the mouse p16INK4a plays a role in tumor suppression. To investigate this problem, a targeting vector pointing to p16INK4a exon 1 alpha with 1.5 kb Eco81 I/Acc II fragment as short arm and 5.9 kb Xba I/Xho I fragment as long arm was built. After linearlization and purification, the targeting vector was introduced into ES cells through electroporation. Thirty-seven G418- and gancyclovir-resistant colonies were picked out and one of them was confirmed as positive by Southern hybridization.

Animals↗
PubMed1988

Characterization of the early region 3 and fiber genes of Ad7.

The nucleotide sequence and the predicted amino acid sequences for open reading frames (ORFs) encoded in the Bam-Hl D fragment of Ad7 (Gomen) DNA show an organization and conservation of potential polypeptides between Ad3 and Ad7. Five ORFs encoded within early region 3 (E3) and shared with the corresponding region of Ad3 can be identified; four of these potential coding regions also share homology to ORFs found in E3 of Ad2 and Ad5. The fiber gene of late region 5 (L5) is also apparent within this region; S1 mapping experiments show that the 5' and 3' boundaries of the main exon in fiber mRNA lie at each end of the proposed fiber ORF. The predicted amino acid sequence for Ad7 fiber shares 60% amino acid homology to Ad3 fiber, but only 20% to Ad2 fiber. Surprisingly, there are three regions of partial amino acid homology near the N- and C-termini of the predicted fiber gene sequences from Ad2, Ad3, Ad5, and Ad7; these conserved regions may be important for interaction with penton base, for proper folding of the shaft of the molecule, or for recognition of the cellular receptor to which adenovirus attaches during infection.

Adenoviruses, Human↗
PubMed1984

The organization and complete nucleotide sequence of the PstI restriction-modification system.

We have determined the nucleotide sequence of a 4.0-kilobase DNA fragment containing the genes of the PstI restriction-modification system. Two large open reading frames were identified within the sequence and were ascribed to the restriction enzyme and methylase by the analysis of a series of deletion mutants. The two genes are encoded on opposite DNA strands, and hence must be transcribed from separate promoters rather than as a polycistronic message. The sequence of the first 10 amino acids of the restriction endonuclease was determined by sequential Edman degradation of the purified protein, permitting the alignment of the polypeptide with the DNA sequence. The NH2 terminus of the modification enzyme was established by sequential Edman degradation of the protein synthesized in bacterial minicells with different radiolabeled amino acids. The initiation codons of the two genes are separated by 130 base pairs. The deduced amino acid sequences indicate that the restriction endonuclease contains 326 amino acids with a calculated Mr = 37,370; the modification enzyme is composed of 507 amino acids with a calculated Mr = 56,830. There is no significant homology between the two proteins at the level of the primary structure. Antibody raised against the purified restriction endonuclease did not immunoprecipitate the modification enzyme. The transcription initiation sites were mapped using mung bean nuclease. Both of the transcripts begin with adenosine. The initiation sites are separated by only 70 base pairs. This close proximity suggests that the promoters for the two divergent genes overlap. DNase I protection experiments show that Escherichia coli RNA polymerase has a higher affinity for the methylase promoter than for the restriction enzyme promoter.

Amino Acid Sequence↗
PubMed1996

A fork head related multigene family is transcribed in Xenopus laevis embryos.

We have isolated and sequenced ten different members of the fork head/HNF-3 multigene family from Xenopus laevis which have been termed Xenopus fork head domain related (XFD) genes 1 to 10. Another four isolated genes (XFD' genes) represent pseudo-allelic variants which arose by an ancient tetraploidization within this species. Whereas all genes of this multigene family exhibit a high degree of sequence homology within the evolutionary conserved fork head domain, sequences outside this module are substantially different. Based upon sequence homologies over the entire coding sequences, XFD-7/7' represent the Xenopus homologs to the rodent hepatocyte nuclear factor HNF-3 alpha, while XFD-3/3' encode the homologs to HNF-3 beta. Here we present an analysis of the temporal transcription pattern of XFD genes 1 to 10 during embryogenesis and in some adult tissues. Eight of these XFD genes are activated during embryonic development, but show different and distinct transcription profiles. The localization of transcripts was determined by whole-mount in situ hybridization. Although transcription of individual XFD genes partially overlaps, each gene is characterized by means of a specific spatial pattern of transcriptional activity.

Amino Acid Sequence↗
PubMed1998

Macrophage activation by polycyclic aromatic hydrocarbons: evidence for the involvement of stress-activated protein kinases, activator protein-1, and antioxidant response elements.

Polycyclic aromatic hydrocarbons (PAH) contained in fossil fuel combustion particles enhance the allergic response to common environmental Ags. A key question is: what are molecular pathways in the immune system by which PAH and conversion products drive allergic inflammation? Circumstantial evidence suggests that macrophages are involved in PAH-induced responses. We demonstrate that a representative PAH, beta-napthoflavone (BNF), and a representative quinone metabolite, tert-butylhydroxyquinone (tBHQ), induce Jun kinase and p38 mitogen-activated protein kinase activities in parallel with the generation of activator protein-1 (AP-1) mobility shift complexes in THP-1 and RAW264.7 macrophage cell lines. Activation of mitogen-activated protein kinases was dependent on generation of oxidative stress, and could be inhibited by N-acetylcysteine. Another genetic response pathway linked to PAH is the antioxidant response element (ARE), which regulates expression of detoxifying enzymes. BNF and tBHQ activated a human ARE (hARE) reporter gene in RAW264.7 cells. Interestingly, bacterial lipopolysaccharide also induced hARE/chloramphenicol acetyltransferase activity. While the hARE core, GTGACTCAGC, contains a consensus AP-1 sequence (underlined), AP-1 was not required for hARE activation. This suggests that PAH and their conversion products operate via ARE-specific transcription factors in the immune system. BNF and tBHQ did, however, induce AP-1 binding to the hARE, while constitutively active Jun kinase interfered in hARE/chloramphenicol acetyltransferase activation. This suggests that AP-1 proteins negatively regulate the hARE. These data establish important activation pathways for PAH in the immune system and provide us with targets to modulate the effect of environmental pollutants on allergic inflammation.

Animals↗
PubMed2006

Extense variant gene family repertoire overlap in Western Amazon Plasmodium falciparum isolates.

In order to find a molecular basis for observations of relatively fast developing immunity to malarial infections in the Western Amazon region, the partial var, stevor and rif gene repertoires of nine different Plasmodium falciparum isolates collected in 1985 and 2000-2004 were evaluated. In contrast to previous results from South East Asia, the variant gene repertoire in Brazilian isolates is rather small and redundant. While the individual var repertoire sizes of Brazilian strains did not differ from Southeast Asian/African isolates, we found an over three times higher overlap of var sequence repertoires in Amazonian strains which was also conserved over time, suggesting the ongoing circulation of a similar var gene repertoire. Coincidently, almost 40% of the sequences identified herein showed the highest degree of similarity to var genes from either Brazilian or Venezuelan isolates, indicating a limited var repertoire of P. falciparum in the Amazon Basin as a whole. The intrastrain similarities of var genes were slightly but significantly lower than in Southeast Asian/African samples suggesting a higher selective pressure for diversification in Amazonian isolates. Despite of higher copy numbers per genome, rif genes also showed a significant repertoire overlap. stevor genes, which share the same predominant subtelomeric localization as var and rif genes, showed a still higher repertoire overlap and were highly similar to 3D7 stevor genes, indicating stronger functional conservation than var and rif genes. This is the first study that reveals that P. falciparum variant gene repertoires of certain areas can be limited. This has important implications for the strain-specific immunity against variant antigens occurring in these areas.

Animals↗
PubMed2002

Overlapping of MINK and CHRNE gene loci in the course of mammalian evolution.

Overlapping of genes, especially in an anti-parallel fashion, is quite rare in eukaryotic genomes. We have found a rare instance of exon overlapping involving CHRNE and MINK gene loci on chromosome 17 in humans. CHRNE codes for the epsilon subunit of the nicotinic acetylcholine receptor (AChRepsilon) whereas MINK encodes a serine/threonine kinase belonging to the GCK family. To elucidate the evolutionary trail of this gene overlapping event, we examined the genomes of a number of primates and found that mutations in the polyadenylation signal of the CHRNE gene in early hominoids led to the overlap. Upon extending this analysis to genomes of other orders of placental mammals, we observed that the overlapping occurred at least three times independently during the course of mammalian evolution. Because CHRNE and MINK are differentially expressed, the potentially hazardous mutations responsible for the exon overlap seem to have escaped evolutionary pressures by differential temporo-spatial expression of the two genes.

Animals↗
PubMed2005

Regulation of insulin gene expression by overlapping DNA-binding elements.

The transcription factor MafA/RIPE3b1 is an important regulator of insulin gene expression. MafA binds to the insulin enhancer element RIPE3b (C1-A2), now designated as insulin MARE (Maf response element). The insulin MARE element shares an overlapping DNA-binding region with another insulin enhancer element A2. A2.2, a beta-cell-specific activator, like the MARE-binding factor MafA, binds to the overlapping A2 element. Our previous results demonstrated that two nucleotides in the overlapping region are required for the binding of both factors. Surprisingly, instead of interfering with each other's binding activity, the MafA and the A2-binding factors co-operatively activated insulin gene expression. To understand the molecular mechanisms responsible for this functional co-operation, we have determined the nucleotides essential for the binding of the A2.2 factor. Using this information, we have constructed non-overlapping DNA-binding elements and their derivatives, and subsequently analysed the effect of these modifications on insulin gene expression. Our results demonstrate that the overlapping binding site is essential for maximal insulin gene expression. Furthermore, the overlapping organization is critical for MafA-mediated transcriptional activation, but has a minor effect on the activity of A2-binding factors. Interestingly, the binding affinities of both MafA and A2.2 to the overlapping or non-overlapping binding sites were not significantly different, implying that the overlapping binding organization may increase the activation potential of MafA by physical/functional interactions with A2-binding factors. Thus our results demonstrate a novel mechanism for the regulation of MafA activity, and in turn beta-cell function, by altering expression and/or binding of the A2.2 factor. Our results further suggest that the major downstream targets of MafA will in addition to the MARE element have a binding site for the A2.2 factor.

Animals↗
PubMed2002

The virological and clinical significance of mutations in the overlapping envelope and polymerase genes of hepatitis B virus.

The potential for hepatitis B virus (HBV) to alter its genome is considerable. This occurs because the virus utilizes a reverse transcription step in replicating the viral genome. Like human immunodeficiency virus, the reverse transcriptase of HBV is error prone and as a consequence of specific selection pressures within a host a population of viral quasispecies emerges. HBV mutants with survival advantages over the wild type virus appear within the selective in vivo environment. Some of these viruses include HBV vaccine escape and anti-viral resistant mutants that have changes in the envelope (S) and polymerase genes, respectively. In addition, the genome of HBV is organised in to overlapping reading frames. The S gene is completely overlapped by the polymerase gene. As a consequence, mutations in the S gene may produce changes in the overlapping polymerase gene. Similarly, mutations in the polymerase gene may produce changes in the S gene. The virological and clinical significance of such overlapping mutations is unclear. However, we have shown that certain mutations in either the S or polymerase gene produce functionally significant changes in the respective overlapping gene. Treatment of chronic hepatitis B carriers with long-term lamivudine (LMV) results in the selection of HBV mutants that are resistant to this nucleoside analogue. The polymerase mutations associated with LMV resistance produce changes in the overlapping S gene and in its envelope protein (hepatitis B small antigen, HBsAg) that results in a reduced antigenicity of the HBsAg protein. The selection of vaccine escape mutants by HBV vaccination or hepatitis B immune globulin is associated with changes in the S gene that are accompanied by mutations in the fingers sub-domain of the polymerase protein. When combined with polymerase mutations that are associated with resistance to LMV the changes within the fingers sub-domain of the viral enzyme behave as compensatory mutations that are able to restore the replication of LMV resistant HBV. The ability to change a viral protein by mutations in an overlapping but unrelated viral gene may produce HBV mutants with altered antigenicity and/or replication and a natural history that may be distinctly different to wild type HBV.

DNA-Directed DNA Polymerase↗
PubMed2005

Probabilistic discovery of overlapping cellular processes and their regulation.

In this paper, we explore modeling overlapping biological processes. We discuss a probabilistic model of overlapping biological processes, gene membership in those processes, and an addition to that model that identifies regulatory mechanisms controlling process activation. A key feature of our approach is that we allow genes to participate in multiple processes, thus providing a more biologically plausible model for the process of gene regulation. We present algorithms to learn each model automatically from data, using only genomewide measurements of gene expression as input. We compare our results to those obtained by other approaches and show that significant benefits can be gained by modeling both the organization of genes into overlapping cellular processes and the regulatory programs of these processes. Moreover, our method successfully grouped genes known to function together, recovered many regulatory relationships that are known in the literature, and suggested novel hypotheses regarding the regulatory role of previously uncharacterized proteins.

Computational Biology↗
PubMed2004

Rituximab induces different but overlapping sets of genes in human B-lymphoma cell lines.

The therapeutic unconjugated anti-CD20 Mab rituximab is used for the treatment of B-non-Hodgkin's lymphomas. We have studied the direct biological effects, signalling and gene expression profiles induced by rituximab in two human B-lymphoma cell lines, DHL4 and BJAB, using microarray, quantitative PCR and gel shift analysis. Rituximab alone inhibited thymidine uptake and induced homotypic adhesion in DHL4 only, but not BJAB. Analysis of Affymetrix microchips carrying probes for about 10,000 human cDNAs, allowed us to identify 16 genes in DHL4 and 12 in BJAB induced by rituximab at 4 h. Eleven and seven of these genes were specific for DHL4 and BJAB, respectively; whereas the remaining five were up-regulated in both cell lines. Mean induction ranged from 2- to 16-fold. Real time PCR analysis allowed us to confirm up-regulation of all genes identified, except one in BJAB. Time course of induction of eight genes was studied, showing peak induction in most cases at 4 h. The up-regulation of 5/5 genes was also observed with the F(ab')(2) fragment of rituximab. Analysis of three further B-cell lymphoma lines showed that gene induction is not restricted to BJAB and DHL4. Finally, we show that rituximab alone can induce AP1 activation in both cell lines and provide evidence that the ERK1/2 pathway is involved in the rituximab-mediated up-regulation of gene expression. These data demonstrate that rituximab alone has direct signalling capacity in different B-lymphoma lines, inducing distinct but overlapping sets of genes which may play a role in the biological and/or therapeutic effect of the antibody.

Antibodies, Monoclonal↗
PubMed2004

[Construction of middle fragment deletion mutant with improved gene splicing by overlap extension].

OBJECTIVE: To construct a phosphatidylinositol 4-kinase beta (PI4K-beta) mutant with the 325th to 373rd amino acid codons deleted, and try to develop a simple method for constructing middle fragment deletion mutant. METHODS: In line with the mechanism of gene splicing by overlap extension(SOE), an additional PCR was used to get the PI4K-beta mutant in which the 325th to 373rd amino acid codons were deleted. Then the mutated gene was cloned into pCMV-Tag4A mammalian expression vector. RESULTS: A mutant with the 325th to 373rd amino acid codons deleted was constructed successfully. CONCLUSION: The improved SOE is a very effective and reliable method to construct middle fragment deletion mutant. It is worthy to be popularized.

1-Phosphatidylinositol 4-Kinase↗
PubMed1980

Morphogenetic genes C and Nu3 overlap in bacteriophage lambda.

In bacteriophage lambda, genes C and Nu3, two of the four cistrons which are essential for normal prohead formation, have overlapping nucleotide sequences. These genes are translated in the same reading frame so that the Nu3 protein is identical to the COOH-terminal one-third of the C protein. This structural relationship may provide for the functional interaction of the C and Nu3 proteins through their regions of structural homology during prohead assembly. The in-phase overlapping organisation of genes may constitute a general strategy to facilitate the mutual interaction of a pair of proteins through their common structural domains.

Bacteriophage lambda↗