Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ten intron mutations and one exon mutation giving rise to defective splicing in the human gene for hypoxanthine phosphoribosyl transferase (hprt) in T-lymphocytes have been characterized. The splicing mutants were detected by PCR amplification of hprt cDNA and direct sequencing. Nine of the mutants showed skipping of whole exons or parts of exons in the cDNA, one mutant had an inclusion of an intron sequence into the cDNA, and one mutant showed both inclusion of an intron sequence and skipping of exons as well as a normal cDNA. Genomic PCR and direct sequencing of the splice sites involved showed one deletion of three base pairs and 10 different single base alterations to be responsible for these splice alterations. One mutation in the last base pair of exon 6 causing skipping of the entire exon 6 was found, whereas an identical mutation in the last base pair of exon 2 caused no aberrant splicing. It was also found that a deletion mutation in the pyrimidine rich stretch of the acceptor site of intron 7 caused skipping of the entire exon 8, whereas a base substitution in the last base of intron 7 caused exclusion of only the first 21 base pairs of exon 8 as a result of the activation of a cryptic acceptor site in exon 8. The results show that many different types of mutations at several different sites can cause splicing errors in the hprt gene and that the sequence differences between the splice sites influence the possible spectrum of mutations in each site.
Environ Mol Mutagen 1992
PMID:Mutations causing defective splicing in the human hprt gene. 138 Apr 58

The solution structure of the alternating pyrimidine-purine DNA duplex [d(GCGTATACGC)]2 has been determined using two-dimensional nuclear magnetic resonance techniques and distance geometry methods. Backbone distance constraints derived from experimental nuclear Overhauser enhancement and J-coupling torsion angle constraints were required to adequately define the conformation of the inter-residue backbone linkages and to avoid underwinding of the duplex. The distance geometry structures were further refined by back-calculation of the two-dimensional nuclear Overhauser enhancement spectra to correct spin-diffusion distance errors. Fifteen final structures for [d(GCGTATACGC)]2 were generated from the refined experimental distance bounds. These structures all exhibit fully wound B-form geometry with small penalty values (< 1.5 A) against the distance bounds and small pair-wise root-mean-square deviation values (typically 0.6 A to 1.5 A). The final structures exhibit positive base-pair inclination with respect to the helix axis, a marked alternation in rise and twist, and are shorter and wider than classical fiber B-form DNA. The purines were found to adopt a sugar pucker close to the C-2'-endo conformation while pyrimidine sugars exhibited significantly lower pseudorotation phase angles in the C-1'-exo to C-2'-endo range. The minor groove cross-strand steric clashes at pyrimidine-purine steps that would exist in pure B-DNA are attenuated by an increased rise at these steps (and an increased roll angle at TpA steps). Concomitantly the backbone torsion angles of the pyrimidine moieties have larger gamma values, larger epsilon values, and smaller zeta values than the purines. The structures generated by distance geometry methods were also compared with those obtained from restrained molecular dynamics with empirical force-field potentials. The results indicate that the nuclear magnetic resonance/distance geometry approach alone is capable of elucidating most of the salient structural features of double-stranded helical nucleic acids in solution without resorting to empirical energy potentials and without using any structural assumptions from crystallographic data.
J Mol Biol 1992 Nov 05
PMID:Solution structure of [d(GCGTATACGC)]2. 144 76

The binding specificity was defined of a human ultraviolet light-damaged DNA recognition protein (UV-DRP), the activity of which is absent in some xeroderma pigmentosum complementation group E cells. Our results suggest that cyclobutane pyrimidine dimers (CPDs) are not high affinity UV-DRP binding sites--a finding consistent with other reports on this protein (Hirschfeld et al., (1990) Mol. Cell Biol., 10, 2041-2048). A major role for 6-4 photoproducts in UV-DRP binding was suggested in studies showing that irradiated oligonucleotides containing a T4C UV box sequence, which efficiently forms a TC 6-4 photoproduct, was a superior substrate for the UV-DRP when compared to a similar irradiated oligonucleotide having a T5 sequence. The latter sequence forms CPDs at a much higher frequency than 6-4 photoproducts. In a more direct approach, T4C-containing oligonucleotides complexed with the UV-DRP were separated from the unbound oligonucleotide fraction and the frequencies of 6-4 photoproducts in the two DNA populations were compared. The UV-DRP-bound fraction was highly enriched for the 6-4 lesion over the unbound fraction supporting the conclusion that 6-4 photoproducts are the principal binding cues for the UV-DRP.
 ...
PMID:An ultraviolet light-damaged DNA recognition protein absent in xeroderma pigmentosum group E cells binds selectively to pyrimidine (6-4) pyrimidone photoproducts. 145 41

Chemical probing of the structures of a few very similar 30 base-pair duplexes containing a 6-O-methylguanine (meG) residue at the 16th position reveals that the modified base simultaneously perturbs the helical structure in two ways; it preferentially unstacks the 3' neighbouring base residue (thymine in this study) on the same strand and it unstacks the pyrimidine to which it is base-paired. Depending on its neighbouring 5' base residue and the base-pairing pyrimidine, this perturbation can extend to a few base-pairs in both 3' and 5' directions from the abnormal base-pair. These perturbations can be detected by cleavage at the site for the restriction enzyme MaeII. The unstaking of the C in the meG.C and A.C base-pairs may explain the de novo methylation of these helices by the human DNA-(cytosine-5-)methyltransferase. Interestingly, the kinetics of repair of the 6-O-methylguanine-containing dinucleotides by the cloned human methylguanine methyltransferase appears to be largely determined by the strength of the stacking interaction between the 6-O-methylguanine and the 5' neighbouring base.
J Mol Biol 1992 Dec 20
PMID:Structure-related properties of the mutagenic lesion 6-O-methylguanine in DNA. 147 83

The metabolism of pyrimidine nucleotides was studied in non-contracting myocytes isolated from adult rat hearts and compared to that observed in freshly prepared myocardium. The myocytes were cultured for up to 96 hrs in a commercial medium containing 50 microM cytidine, uridine, adenosine and adenine; 20 microM guanosine, thymidine and D-ribose; and 5 microM hypoxanthine, xanthine, guanine, thymine and uracil. Nucleotide pool sizes were measured by HPLC. Nucleotide and RNA labelling were followed by incorporation of [U-14C]-cytidine or [U-14C]-uridine added in trace amounts to the medium. The adenine nucleotide pool was 2.4-fold larger than in situ after 7 hrs of incubation and then returned to values 30% higher than that found in the myocardium after 25 hrs. Cytosine and uracil nucleotide pools after 25 hrs of culture were respectively 2 and 4-fold larger than in situ and remained at these levels thereafter. Intracellular cytidylate and uridylate equilibrated very rapidly with exogenous [U-14C]-cytidine but not with [U-14C]-uridine. We conclude that, under the experimental conditions used here, the synthesis of pyrimidine nucleotides in isolated myocytes is mainly supplied by exogenous nucleosides. Furthermore, extracellular cytidine is rapidly converted to both uracil and cytosine nucleotides while uridine serves only as the precursor for uracil nucleotide synthesis.
J Mol Cell Cardiol 1992 Nov
PMID:Pyrimidine nucleotide synthesis is preferentially supplied by exogenous cytidine in adult rat cultured cardiomyocytes. 147 25

A novel type of triple-stranded DNA structure was proposed by several groups to play a crucial role in homologous recognition between single- and double-stranded DNA molecules. In this still putative structure a duplex DNA was proposed to co-ordinate a homologous single strand in its major groove side. In contrast to the well-characterized pyrimidine-purine-pyrimidine triplexes in which the two like strands are antiparallel and which are restricted to poly-pyrimidine-containing stretches, the homology-specific triplexes would have like strands in parallel orientation and would not be restricted to any particular sequence provided that there is a homology between interacting DNA molecules. For many years the stereo-chemical possibility of forming homology-dependent three- or four-stranded DNA structures during the pairing stage of recombination reactions was seriously considered in published papers. However, only recently has there been a marked increase in the number of papers that have directly tested the formation of triple-stranded DNA structures during the actual pairing stage of the recombination reaction. Unfortunately the results of these tests are not totally clear cut; while some laboratories presented experimental evidence consistent with the formation of triplexes, others studying the same or very similar systems offered alternative explanations. The aim of this review is to present the current state of the central question in the mechanism of homologous recombination, namely, what kind of DNA structure is responsible for DNA homologous recognition. Is it a novel triplex structure or just a classical duplex?
Mol Microbiol 1992 Nov
PMID:Three-stranded DNA structure; is this the secret of DNA homologous recognition? 148 82

Theoretical studies of the sequence-dependent conformation of B-DNA have been carried out using Jumna, a helicoidal co-ordinate minimization algorithm. The results obtained for a series of six oligomers with repetitive sequences show that, with the exception of the homopolymers (dA)n.(dT)n and (dG)n.(dC)n, all sequences can adopt a variety of conformations characterized by considerable changes in helicoidal parameters and also in sugar puckers which adopt C(2')-endo (falling into 2 classes) or, in the case of pyrimidine nucleotides, O(1')-endo forms. These studies lead to an improved understanding of the role of base sequence on DNA conformation and point to a number of interesting correlations between the various structural parameters describing the double helix.
J Mol Biol 1992 Aug 05
PMID:Conformational sub-states in B-DNA. 150 26

Expression of the lacZ gene in Escherichia coli is inactivated by exposure to ultraviolet light (UV). Inactivation is exceptionally effective when cells contain amplified levels of DNA photolyase (which forms complexes with pyrimidine dimers in the absence of light for actual photoreversal) and a lambda prophage. Without amplified photolyase, the lambda prophage or both, inactivation rates are similar and much lower. UV-inactivation of lacZ gene expression in the presence of both amplified photolyase and lambda is even more effective if lambda cI857 is used in place of the wildtype prophage but is wholly unexceptional if the prophage carries defects in the lambda genes rexA or rexB. When Rex AB proteins are provided by expression from a plasmid and the cell also contains amplified photolyase, exceptional inactivation rates again obtain; in fact inactivation is most effective under these conditions. The data are considered to reveal a role for Rex AB proteins, which mediate superinfection exclusion, in the exceptional inactivation of gene expression by photolyase bound to pyrimidine dimers in DNA. Photolyase-dimer complexes may mimic the structure of certain complexes that arise during phage development and thus influence Rex A and/or B proteins, thereby shutting down cell metabolism.
Mol Gen Genet 1992 Feb
PMID:RexAB proteins of bacteriophage lambda enhance the effect of photolyase-dimer complexes on lacZ gene expression in Escherichia coli. 153 92

We have investigated the characteristics of the receptor for ATP on neuronal cells and the involvement of phospholipase C and phospholipase D in the effector mechanisms, using PC12 rat phaeochromocytoma cells in culture. We show that the cells respond, with generation of total inositol phosphates, to ATP and adenosine 5'-O-(3-thiotriphosphate) (ATP gamma S) but not to 2-methylthioadenosine5'-triphosphate (2MeSATP), beta,gamma-methylene ATP, or adenosine 5'-O-(2-thiodiphosphate) (ADP beta S). The largest response to ATP gamma S was mainly independent of extracellular calcium, had an EC50 of 7.93 +/- 0.76 microM, and was competitively inhibited by the nonspecific antagonist suramin. The pyrimidine nucleotide UTP also elicited a response in these cells. Measurement of [3H]inositol triphosphate showed a rapid rise to maximum (10-15 sec) in response to both ATP gamma S and UTP but no response to 2MeSATP. Cells prelabeled with 32Pi and stimulated in the presence of 50 mM butanol responded to ATP gamma S, ATP, and UTP with enhanced formation of [32P]phosphatidylbutanol as well as [32P]phosphatidic acid, indicating that agonist-stimulated phosphatidic acid occurs by both phospholipase D and phospholipase C activity. The stimulation of phospholipase D was inhibited by the presence of a protein kinase C inhibitor, Ro 31-8220. The dose-response curve for the stimulation by ATP gamma S of phospholipase C was shifted to the right by the presence of UTP, indicating that both compounds act on the same receptors. The data provide the first evidence for the existence of a nucleotide receptor on neuronal cells (insensitive to both purines and pyrimidines) and show that this receptor is linked to both phospholipase C and phospholipase D.
Mol Pharmacol 1992 Mar
PMID:Neuronal "nucleotide" receptor linked to phospholipase C and phospholipase D? Stimulation of PC12 cells by ATP analogues and UTP. 154 77

The DNA in dormant spores of Bacillus species is associated with alpha/beta-type small, acid-soluble proteins (SASP), which are double-stranded DNA-binding proteins whose amino acid sequence has been highly conserved in evolution. In vitro these proteins bind most strongly to DNA which readily adopts an A-like conformation, as binding of alpha/beta-type SASP causes DNA to assume an A-like conformation. As predicted by this conformational change in DNA, binding of alpha/beta-type SASP to relaxed but covalently closed plasmid DNA results in the introduction of a large number of negative supercoils. Associated with the conformational change in DNA brought about by alpha/beta-type SASP binding is a change in its photochemistry such that ultraviolet irradiation does not generate pyrimidine dimers, but rather a thyminyl-thymine adduct termed spore photoproduct (SP). The latter two properties of DNA complexed with alpha/beta-type SASP in vitro are similar to those of DNA in dormant spores of Bacillus species in which: (i) plasmid DNA has a much higher number of negative supercoils than plasmid in growing cells; and (ii) ultraviolet irradiation produces SP and no pyrimidine dimers, while only pyrimidine dimers are formed in growing cells. During sporulation these changes in the properties of spore DNA take place in parallel with synthesis of alpha/beta-type SASP, and the magnitude of the changes is greatly reduced in mutants that make low amounts of these proteins. A straightforward interpretation of these data is that DNA in dormant spores of Bacillus species is in an A-like conformation.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Microbiol 1992 Mar
PMID:DNA in dormant spores of Bacillus species is in an A-like conformation. 155 55


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>