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Query: UNIPROT:P06889 (Mol)
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New cellular traits of Cockayne's syndrome (CS) associated with DNA precursor metabolism have been identified, namely, hypersensitivity to the toxicity of low concentrations of deoxyguanosine (dG) and abnormal changes in deoxyribonucleotide (dNTP) pools in response to dG or UV. dG treatment results in similar ribonucleotide pool changes in wild-type and CS cells, i.e., GTP levels increase at least twofold. However, the changes in the pool size of the purine deoxyribonucleotides are significantly different; in wild-type cells dATP and dGTP pools increase threefold, but remain unchanged in CS. The mechanism by which dG kills CS cells is not clear, but unlike the inherited purine nucleoside phosphorylase deficiency disease, the toxicity of dG is not due to the accumulation of dGTP and the consequent feedback inhibition of ribonucleotide reductase. UV induces different dNTP pool changes in CS and wild-type cells. In wild-type cells dTTP, dCTP, and dATP pools increase three- to fivefold within 4 h of irradiation, while the dGTP pool contracts. In CS cells, only the dGTP pool expands (four- to sixfold), while the other three contract. Each of these new phenotypic traits, together with UV sensitivity, is coordinately corrected in the complementing proliferating CSA x CSB hybrid cells.
Somat Cell Mol Genet 1992 Sep
PMID:Cockayne's syndrome fibroblasts are characterized by hypersensitivity to deoxyguanosine and abnormal DNA precursor pool metabolism in response to deoxyguanosine or ultraviolet light. 147 5

A detailed comparative study of the regions surrounding the origin of replication in vertebrate mitochondrial DNA (mtDNA) has revealed a number of interesting properties. This region, called the D-loop-containing region, can be divided into three domains. The left (L) and right (R) domains, which have a low G content and contain the 5' and the 3' D-loop ends, respectively, are highly variable for both base sequence and length. They, however, contain thermodynamically stable secondary structures which include the conserved sequence blocks called CSB-1 and TAS which are associated with the start and stop sites, respectively, for D-loop strand synthesis. We have found that a "mirror symmetry" exists between the CSB-1 and TAS elements, which suggests that they can act as specific recognition sites for regulatory, probably dimeric, proteins. Long, statistically significant repeats are found in the L and R domains. Between the L and R domains we observed in all mtDNA sequences a region with a higher G content which was apparently free of complex secondary structure. This central domain, well preserved in mammals, contains an open reading frame of variable length in the organisms considered. The identification of common features well preserved in evolution despite the high primary structural divergence of the D-loop-containing region of vertebrate mtDNA suggests that these properties are of prime importance for the mitochondrial processes that occur in this region and may be useful for singling out the sites on which one should operate experimentally in order to discover functionally important elements.
J Mol Evol 1987
PMID:Structural elements highly preserved during the evolution of the D-loop-containing region in vertebrate mitochondrial DNA. 312 68

The nucleotide sequences of the D-loop-containing regions of three rat mitochondrial DNAs (mtDNAs), two from the species Rattus norvegicus and one from R. rattus, were determined. Comparisons made among these sequences and with the mouse sequence showed that, on the basis of both base composition and frequency of nucleotide alterations, three domains could be defined within the D-loop-containing region: a central conserved segment, poor in L-strand adenine, flanked by two divergent, adenine-rich regions. Deletions and insertions were found to occur at an unexpectedly high frequency in these sequences and the conserved sequence block called CSB-1 was found not to be intact in the R. rattus sequence. Although in comparisons of more distantly related mtDNAs the D-loop region is the most divergent on the molecule, it does not diverge more than typical protein genes between R. norvegicus and R. rattus, and its central conserved domain appears to be one of the molecule's most conserved regions. The most variable domain borders the tRNAPhe gene and contains the L and H-strand promoters and the 5' terminus for H-strand DNA synthesis. Within this region we have found sequences in all the mtDNAs we have examined, including those of human, two artiodactyls and Xenopus, that are capable of folding into cloverleaf structures. In the other divergent domain of the same mtDNAs, we find sequences capable of assuming similar secondary structural configurations at or near the sites for the termination of D-loop DNA synthesis. The evolutionary preservation of the potential to form such structures despite the high primary-structural divergence of the regions they occur in, suggests the structures are of principal importance for some processes occurring in the D-loop-containing region.
J Mol Biol 1986 Dec 05
PMID:Structural conservation and variation in the D-loop-containing region of vertebrate mitochondrial DNA. 356 Feb 25

ACTH-dependent transcriptional activation of the bovine CYP17 gene (the gene encoding cytochrome P450 steroid 17 alpha-hydroxylase) involves two cAMP-responsive sequences (CRS1 and CRS2) located in the promoter region. Here we demonstrate that two nuclear orphan receptors, chicken ovalbumin upstream promoter transcription factor (COUP-TF) and steroidogenic factor-1 (SF-1), bind to the part of the CRS2 element that contains the repeated sequences AAGTCA and AGGTCA spaced by six nucleotides (repCRS2). Overexpression of COUP-TF and SF-1 in both steroidogenic and nonsteroidogenic cells demonstrated that SF-1 is an activator of repCRS2-dependent transcription of reporter genes. Furthermore, the SF-1-dependent transcription could be further stimulated by activation of the cAMP-dependent protein kinase. In contrast, COUP-TF alone had no effect on repCRS2-dependent reporter gene activity. Mutations that interfere with the binding of SF-1 to repCRS2 in vitro abolished the cAMP-induced activities mediated by the element in transfected Y1 cells. The mutational analysis of repCRS2 further indicated that the binding sites for the two receptors overlap, and electrophoretic mobility shift assays demonstrated that the receptors bound in a mutually exclusive manner. Overexpression of both SF-1 and COUP-TFI simultaneously demonstrated that COUP-TFI inhibited SF-1-dependent activation of reporter genes. Transient transfection experiments with a construct containing a -100/+19 base pair fragment from the bovine CYP17 gene demonstrated that SF-1 and COUP-TF had similar effects on the intact promoter as on the repCRS2/reporter gene constructs. Our data suggest that the two orphan receptors bind in a mutually exclusive manner to repCRS2 and that SF-1 is involved in the activation and COUP-TF in the repression of repCRS2-dependent transcription.
Mol Endocrinol 1995 Mar
PMID:Mutually exclusive interactions of two nuclear orphan receptors determine activity of a cyclic adenosine 3',5'-monophosphate-responsive sequence in the bovine CYP17 gene. 777 79

By cloning and sequencing 3.4 kilobases of snow goose mtDNA we found that the ND5 gene is followed by the genes for cytochrome b, tRNA(Thr), tRNA(Pro), ND6, tRNA(Glu), the control region, tRNA(Phe), and srRNA. This order is identical to that of chicken, quail, and duck mtDNA but differs from that of mammals and a frog (Xenopus). The mean extent of difference due to base substitution between goose and chicken is generally closer to the same comparison between rat and mouse but less than that between human and cow. For one of the nine regions compared (tRNA(Glu)), the bird differences appear to be anomalous, possibly implicating altered functional constraints. Within the control region, several short sequences common to mammals are also conserved in the birds. Comparison of the goose control region with that of quail and chicken suggests that a sequence element with similarity to CSB-1 duplicated once prior to the divergence of goose and chicken and again on the lineage leading to chicken. Between goose (or duck) and chicken there are four times more transversions at the third positions of fourfold-degenerate codons in mitochondrial than in nuclear genes.
J Mol Evol 1993 Oct
PMID:Sequence evolution in and around the mitochondrial control region in birds. 830 9

The nucleotide excision repair (NER) pathway is thought to consist of two subpathways: transcription-coupled repair, limited to the transcribed strand of active genes, and global genome repair for nontranscribed DNA strands. Recently we cloned the RAD26 gene, the Saccharomyces cerevisiae homolog of human CSB/ERCC6, a gene involved in transcription-coupled repair and the disorder Cockayne syndrome. This paper describes the analysis of yeast double mutants selectively affected in each NER subpathway. Although rad26 disruption mutants are defective in transcription-coupled repair, they are not UV sensitive. However, double mutants of RAD26 with the global genome repair determinants RAD7 and RAD16 appeared more UV sensitive than the single rad7 or rad16 mutants but not as sensitive as completely NER-deficient mutants. These findings unmask a role of RAD26 and transcription-coupled repair in UV survival, indicate that transcription-coupled repair and global genome repair are partially overlapping, and provide evidence for a residual NER modality in the double mutants. Analysis of dimer removal from the active RPB2 gene in the rad7/16 rad26 double mutants revealed (i) a contribution of the global genome repair factors Rad7p and Rad16p to repair of the transcribed strand, confirming the partial overlap between both NER subpathways, and (ii) residual repair specifically of the transcribed strand. To investigate the transcription dependence of this repair activity, strand-specific repair of the inducible GAL7 gene was investigated. The template strand of this gene was repaired only under induced conditions, pointing to a role for transcription in the residual repair in the double mutants and suggesting that transcription-coupled repair can to some extent operate independently from Rad26p. Our findings also indicate locus heterogeneity for the dependence of transcription-coupled repair on RAD26.
Mol Cell Biol 1996 Feb
PMID:Double mutants of Saccharomyces cerevisiae with alterations in global genome and transcription-coupled repair. 855 76

In this study, the nucleotide sequences of the displacement loop (D-loop) and the ribosomal RNA genes of mitochondrial DNA (mtDNA) were determined from a representative each of two genera of ducks, Cainina muschata and Anas platyrhynchos. The duck mtDNA shows a specific gene order at 5' upstream of D-loop (5'ND6-tRNA(Glu)-D-loop3') that is identical to chick mtDNA but is different from that of mammalian or amphibian (5' cytochrome b-tRNA(Thr)-tRNA(Pro)-D-loop3'). Nucleotide diversity is greatest in the D-loop while being most conserved in the 12S rRNA gene, as indicated from a sequence comparison between duck and chick mtDNA. A consensus sequence in the D-loop region, which may play influential roles in the regulation of transcription and replication of mtDNA, was found in both CSB-1 and repeated sequences of birds. Sequences of four tRNA genes in this region are also reported. Among them, tRNA(Glu) shows the greatest sequence divergence when different order of birds are compared.
Comp Biochem Physiol B Biochem Mol Biol 1996 Oct
PMID:Sequences and comparisons of duck mitochondrial DNA control regions. 893 1

17alpha-Hydroxylase cytochrome P450 (P450(17alpha)) is the enzyme which synthesizes C19 steroids in a two-step reaction in which 17alpha-OH pregnenolone is an intermediate. In the bovine and human adult female, 17alpha-hydroxylase is expressed in adrenocortical cells where 17alpha-OH pregnenolone and 17alpha-OH progesterone are precursors of cortisol, and in theca cells of the ovary where these intermediates are precursors of C19 steroids. In both adrenal cortex and theca, 17alpha-hydroxylase gene expression is stimulated by cyclic AMP (cAMP). The aim of this study was to determine the mechanism regulating 17alpha-hydroxylase gene expression in the bovine ovary. Our results indicate that the bovine 17alpha-hydroxylase gene is regulated in a tissue-specific fashion. Primer extension and S1 nuclease protection assays reveal that the start site of transcription in the theca is identical to that in the adrenal. Transfection studies employing beta-globin reporter gene constructs fused to successive deletions of the 5' regulatory region of the bovine 17alpha-hydroxylase gene indicate that sequences between -80 and -37 basepairs (bp) (CRS2) confer cAMP-regulated transcription in bovine theca cells in culture. These results are in contrast to similar studies conducted in bovine adrenocortical cells, which indicate that the major cAMP response element (referred to as CRS1) is located at -243 to -225 bp. The Ad4 element (AGGTCA, -42 to -37 bp) within CRS2, which has been shown to be involved in cAMP responsiveness in other steroidogenic P450 genes, cannot by itself confer cAMP-regulated reporter gene expression in bovine cells. These results indicate that in the cow, 17alpha-hydroxylase gene expression is regulated in a tissue-specific fashion, and that this regulation may be conferred, at least in part, by the use of tissue-specific cis-acting elements in the bovine 17alpha-hydroxylase gene.
J Steroid Biochem Mol Biol 1996 Sep
PMID:17alpha-Hydroxylase gene expression in the bovine ovary: mechanisms regulating expression differ from those in adrenal cells. 900 34

We sequenced the entire control region and portions of flanking genes (tRNA(Phe), tRNA(Glu), and ND6) in the common chaffinch (Fringilla coelebs), blue chaffinch (F. teydea), brambling (F. montifringilla), and greenfinch (Carduelis chloris). In these finches the control region is similar in length (1,223-1,237 bp) and has the same flanking gene order as in other birds, and contains a putative TAS element and the highly conserved CSB-1 and F, D, and C boxes recognizable in most vertebrates. Cloverleaf-like structures associated with the TAS element at the 5' end and CSB-1 at the 3' end of the control region may be involved with the stop and start of D-loop synthesis, respectively. The pattern of nucleotide and substitution bias is similar to that in other vertebrates, and consequently the finch control region can be subdivided into a central, conserved G-rich domain (domain II) flanked by hypervariable 5'-C-rich (domain I) and 3'-AT-rich (domain III) segments. In pairwise comparisons among finch species, the central domain has unusually low transition/transversion ratios, which suggests that increased G + T content is a functional constraint, possibly for DNA primase efficiency. In finches the relative rates of evolution vary among domains according to a ratio of 4.2 (domain III) to 2.2 (domain I) to 1 (domain II), and extensively among sites within domains I and II. Domain I and III sequences are extremely useful in recovering intraspecific phylogeographic splits between populations in Africa and Europe, Madeira, and a basal lineage in Nefza, Tunisia. Domain II sequences are highly conserved, and are therefore only useful in conjunction with sequences from domains I and III in phylogenetic studies of closely related species.
Mol Biol Evol 1997 Feb
PMID:Structural conservation and variation in the mitochondrial control region of fringilline finches (Fringilla spp.) and the greenfinch (Carduelis chloris). 902 95

The mitochondrial control region (CR) sequence, also known as the D-loop, has been determined for six Cervidae (Artiodactyla, Ruminantia): the red and fallow deers (subfamily Cervinae), the brocket deer and two roe deers (subfamily Odocoileinae), and the Chinese water deer (Hydropotinae). These new sequences have been aligned with available cervid and bovid orthologues. Comparative analyses indicate that the 5'-peripheral domain exhibits a 75-bp length polymorphism near sequences associated with the termination of the H-strand replication. The New World Odocoileinae possess the longest cervid CR due to the presence of an additional 47-bp tandem repeat, located in the 3'-peripheral domain, downstream of the initiation site for H-strand replication (OH) and the first conserved sequence block (CSB-1). This insertion represents a duplication spanning the OH to CSB-1 region and constitutes an exclusive synapomorphy for New World Odocoileinae. Phylogenetic analyses of the complete CR support the paraphyly of antlered deers due to the nesting of the antlerless Hydropotes within Odocoileinae. Capreolus is the closest relative of Hydropotes, and the divergence of this Old World Odocoileinae clade may have occurred between 8.7 and 10.4 MYA. The conserved central domain of CR can be aligned across ungulates and indicates the Pecora monophyly, their close association with cetaceans, and the earlier emergence of suiformes.
Mol Biol Evol 1997 Nov
PMID:The mitochondrial control region of Cervidae: evolutionary patterns and phylogenetic content. 936 73


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