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

Bloom syndrome is more common in individuals of Ashkenazi Jewish descent than in any other population, and one particular mutation in the Bloom syndrome gene, blmAsh, is homozygous in nearly all Ashkenazi Jewish persons with Bloom syndrome. We have determined the frequency of blmAsh in 1491 Ashkenazi Jewish persons with no known history of Bloom syndrome and found that 1 in 107 persons was heterozygous. Although not common, genetic screening for Bloom syndrome is feasible in this population.
Mol Genet Metab 1998 Aug
PMID:Carrier frequency of the Bloom syndrome blmAsh mutation in the Ashkenazi Jewish population. 975 20

The nuclear localization signal (NLS) of the DNA helicase involved in Werner's syndrome (WS) was studied. Previously, we noted that the C-terminal region of WS helicase contains the NLS. In this study, we generated in HeLa cells various chimeric proteins consisting of the N-terminal tagged with an enhanced green fluorescent protein and the C-terminal fragments of the WS helicase that were truncated either from N- or C-termini, and we examined the ability of fragments to transfer the fusion proteins to the nucleoplasm by fluorescence microscopy. A small C-proximal region containing 34 amino acid residues (residues 1369-1402) was found to contain full nuclear migration activities. Subsequent amino acid substitution experiments showed that a sequence of three positively charged amino acids (Lys1371-Arg1372-Arg1373) in this region are particularly important. Similar sequence has previously been defined as the nuclear localization signal of SV-40 large T antigen that also acts as a viral DNA helicase. Conservation of this motif was found in the C-terminal regions of the other RecQ type DNA helicases, including murine WS helicase, yeast sgs1 and rqh+1 and human Bloom syndrome DNA helicases.
Int J Mol Med 1998 Jan
PMID:Characterization of the nuclear localization signal in the DNA helicase involved in Werner's syndrome. 985 1

Bloom syndrome (BS) is a rare autosomal recessive disorder characterized by growth deficiency, immunodeficiency, genomic instability, and the early development of cancers of many types. BLM, the protein encoded by BLM, the gene mutated in BS, is localized in nuclear foci and absent from BS cells. BLM encodes a DNA helicase, and proteins from three missense alleles lack displacement activity. BLM transfected into BS cells reduces the frequency of sister chromatid exchanges and restores BLM in the nucleus. Missense alleles fail to reduce the sister chromatid exchanges in transfected BS cells or restore the normal nuclear pattern. BLM complements a phenotype of a Saccharomyces cerevisiae sgs1 top3 strain, and the missense alleles do not. This work demonstrates the importance of the enzymatic activity of BLM for its function and nuclear localization pattern.
Mol Biol Cell 1999 Mar
PMID:The DNA helicase activity of BLM is necessary for the correction of the genomic instability of bloom syndrome cells. 1006 10

Saccharomyces cerevisiae Sgs1 protein is a member of the RecQ DNA helicase family which also includes the products of the human Bloom's syndrome and Werner's syndrome genes. We have studied the substrate specificity of a recombinant Sgs1 helicase (amino acid residues 400-1268 of the Sgs1 protein). Sgs1 shows a strong preference for binding branched DNA substrates, including duplex structures with a 3' single-stranded overhang and DNA junctions with multiple branches. Duplex DNA with a 5' rather than a 3' single-stranded tail is not recognized or unwound by Sgs1. DNase I and hydroxyl radical footprinting of the Sgs1-DNA complex shows that the protein binds specifically to the junction of a double-stranded DNA and its 3' overhang. Binding and unwinding of duplex DNA with a 3' overhang are much reduced if the backbone polarity of the 3' overhang is reversed in the junction region, but are unaffected if polarity reversal occurs four nucleotides away from the junction. These results indicate that the 3' to 5' polarity of unwinding by the recombinant Sgs1 protein is a direct consequence of the binding of the helicase to the single-stranded/double-stranded DNA junction and its recognition of the polarity of the single-stranded DNA at the junction. The recombinant Sgs1 also unwinds four-way junctions (synthetic Holliday junctions), a result that may be significant in terms of its role in suppressing DNA recombination in vivo.
J Mol Biol 1999 Jun 04
PMID:Binding specificity determines polarity of DNA unwinding by the Sgs1 protein of S. cerevisiae. 1036 2

High-alkaline serine proteases have been successfully applied as protein degrading components of detergent formulations and are subject to extensive protein engineering efforts to improve their stability and performance. Dynamics has been suggested to play an important role in determining enzyme activity and specificity and it is therefore of interest to establish how local changes in internal mobility affect protein stability, specificity and performance. Here we present the dynamic properties of the 269 residue serine proteases subtilisin PB92 (Maxacal(TM)) and subtilisin BLS (Savinase(TM)), secreted by Bacillus lentus, and an engineered quadruple variant, DSAI, that has improved washing performance. T1, T2 and heteronuclear NOE measurements of the 15N nuclei indicate that for all three proteins the majority of the backbone is very rigid, with only a limited number of residues being involved in local mobility. Many of the residues that constitute the S1 and S4 pockets, determining substrate specificity, are flexible in solution. In contrast, the backbone amides of the residues that constitute the catalytic triad do not exhibit any motion. Subtilisins PB92, BLS and DSAI demonstrate similar but not identical NMR relaxation rates. A detailed analysis of local flexibility indicates that the motion of residues Thr143 and Ala194 becomes more restricted in subtilisin BLS and DSAI. Noteworthy, the loop regions involved in substrate binding become more structured in the engineered variant as compared with the two native proteases, suggesting a relation between altered dynamics and performance. Similar conclusions have been established by X-ray crystallograpic methods, as shown in the accompanying paper.
J Mol Biol 1999 Sep 10
PMID:Altered flexibility in the substrate-binding site of related native and engineered high-alkaline Bacillus subtilisins. 1049 61

Genomic instability in its broadest sense is a feature of virtually all neoplastic cells. In addition to the mutations and/or gene amplifications that appear to be a prerequisite for the acquisition of a neoplastic phenotype, human cancers exhibit other "markers" of genomic instability--in particular, a high degree of aneuploidy. Indeed, many studies have shown that aneuploidy is an almost invariant feature of cancer cells, and it has been argued by some that the emergence of aneuploid cells is a necessary step during tumorigenesis. The functional link between genomic instability and cancer is strengthened by the existence of several "genetic instability" disorders of humans that are associated with a moderate to severe increase in the incidence of cancers. These disorders include ataxia telangiectasia, Bloom's syndrome, Fanconi anemia, xeroderma pigmentosum, and Nijmegen breakage syndrome, all of which are very rare and are inherited in a recessive manner. Analysis of the cells from such cancer-prone individuals is clearly a potentially fruitful approach for delineating the genetic basis for instability in the genome. It is assumed that by identifying the underlying cause of genetic instability in these disorders, one can derive valuable information not only about the basis of particular genetic diseases, but also about the underlying causes of genomic instability in sporadic cancers in the general population. In this article, we review the clinical and cellular properties of genetic instability disorders associated with cancer predisposition. In particular, we focus on the rapid advances made in our understanding of these disorders that have derived from the cloning of the genes mutated in each case. Because in many instances the affected genes have analogs in lower eukaryotic species, we shall discuss how studies in yeasts in particular have proved valuable in our understanding of human diseases and predisposition to cancer.
Prog Nucleic Acid Res Mol Biol 1999
PMID:Genetic disorders associated with cancer predisposition and genomic instability. 1050 32

The Bloom (BLM) and Werner's (WRN) syndrome proteins may regulate recombination and DNA repair. Using a novel polyclonal antibody to human BLM, we detected the 170-kda BLM antigen in wild-type but not Bloom syndrome cells. BLM was localized to punctate nuclear structures. The level of BLM but not WRN was 3.6 fold-higher in G(1)/S-synchronized fibroblasts than in G(0)-synchronized fibroblasts. BLM-positive cells invariably expressed topoisomerase IIalpha, whereas topoisomerase IIbeta was expressed constitutively. Transfections of BLM deletion mutants demonstrated that the C-terminal domain of BLM mediated nuclear entry and the central helicase domain was necessary for producing the punctate pattern. By subcellular fractionation, BLM was found primarily in high-salt extracts of the nucleoplasm and the nuclear matrix and was enriched in G(1)/S-synchronized cells compared with G(0)-synchronized cells. There was no interaction between BLM and WRN or topoisomerases IIalpha and IIbeta in fibroblasts. These results demonstrate that BLM is targeted to specific nuclear structures and that its expression is enhanced during cell growth. The known nucleolar localization of WRN, its invariant expression during the cell cycle, and the lack of interaction between BLM and WRN suggest distinct roles for BLM and WRN in processes such as DNA repair and recombination.
Mol Carcinog 1999 Dec
PMID:Localization of the Bloom syndrome helicase to punctate nuclear structures and the nuclear matrix and regulation during the cell cycle: comparison with the Werner's syndrome helicase. 1056 3

Bloom syndrome (BS) is characterized by genomic instability and cancer susceptibility caused by defects in BLM, a DNA helicase of the RecQ-family (J. German and N. A. Ellis, The Genetic Basis of Human Cancer, pp. 301-316, 1998). RecQ helicases and topoisomerase III proteins interact physically and functionally in yeast (S. Gangloff et al., Mol. Cell. Biol., 14: 8391-8398, 1994) and in Escherichia coli can function together to enable passage of double-stranded DNA (F. G. Harmon et al., Mol. Cell, 3: 611-620, 1999). We demonstrate in somatic and meiotic human cells an association between BLM and topoisomerase IIIalpha. These proteins colocalize in promyelocytic leukemia protein nuclear bodies, and this localization is disrupted in BS cells. Thus, mechanisms by which RecQ helicases and topoisomerase III proteins cooperate to maintain genomic stability in model organisms likely apply to humans.
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PMID:Association of the Bloom syndrome protein with topoisomerase IIIalpha in somatic and meiotic cells. 1072 66

Previous studies have shown that acute ethanol administration induces expression of c-Fos immunoreactivity in the central nucleus of the amygdala (CNA) [S.L. Chang, N.A. Patel, A.A. Romero, Activation and desensitization of Fos immunoreactivity in the rat brain following ethanol administration, Brain Res., 679 (1995) 89-98; M. Morales, J.R. Criado, P.P. Sanna, S.J. Henriksen, F.E. Bloom, Acute ethanol induces c-fos immunoreactivity in GABAergic neurons of the central nucleus of the amygdala, Brain Res., 798 (1998) 333-336; A.E. Ryabinin, J.R. Criado, S.J. Henriksen, F.E. Bloom, M.C. Wilson, Differential sensitivity of c-Fos expression in hippocampus and other brain regions to moderate and low doses of alcohol, Mol. Psychiatry, 2 (1997) 32-43]. We recently showed that over 70% of these c-Fos immunoreactive neurons are GABAergic [M. Morales, J.R. Criado, P.P. Sanna, S.J. Henriksen, F.E. Bloom, Acute ethanol induces c-fos immunoreactivity in GABAergic neurons of the central nucleus of the amygdala, Brain Res, 798 (1998) 333-336]. In the present study, we report that ethanol-induced c-Fos immunoreactivity was mainly confined to neurons that express pro-enkephalin (ENK). In contrast, a small number of c-Fos immunoreactive neurons express corticotrophin releasing factor (CRF). Our results thus provide anatomical evidence indicating that within the amygdala, GABAergic neurons that contain ENK are responsive to acute ethanol exposure.
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PMID:Acute ethanol induction of c-Fos immunoreactivity in pre-pro-enkephalin expressing neurons of the central nucleus of the amygdala. 1075 79

Bloom syndrome (BS) is a rare genetic disorder characterized by small body size, photosensitivity, immunodeficiency and a high predisposition to various types of cancer. BLM was identified as the causative gene for BS. The BLM protein is homologous to DNA helicase and has two basic amino acid clusters in its C-terminal region. Previously, we reported that the distal arm of these basic amino acids clusters in the BLM protein functioned as the nuclear localization signal (NLS) of the protein. In this study, we generated plasmid constructs for expression of enhanced green fluorescent protein (EGFP) fused with various BLM protein variants having a mutation with deletions or substitutions in the basic amino acid and analyzed the subcellular localization of the expressed proteins. The EGFP-fused protein containing the basic amino acid cluster region proximal to the C-terminus of BLM helicase was localized exclusively in the nucleus. However, the EGFP-BLM proteins that lacked either Arg1344 or Lys1346 distributed in both the cytoplasm and the nucleus equally. Deletion of Arg1347 also resulted in localization in both the nucleus and cytoplasm, and substitution of Arg1344, Lys1346, Arg1347 or Arg1348 with non-basic amino acids reduced the nuclear localization of BLM protein. Mouse BLM protein which also migrate to the nucleus has two basic amino acid clusters in the C-terminus and the basic amino acids (Lys1346-Pro1347-Lys1348-Arg1349-Arg1350) proximal to the C-terminus are conserved between mouse and human. These findings suggest that the Arg1344-Ser1345-Lys1346-Arg1347 sequence at the C-terminus of the human BLM protein is essential for nuclear localization of this protein.
Int J Mol Med 2000 May
PMID:Characterization of the nuclear localization signal in the DNA helicase responsible for Bloom syndrome. 1076 50


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