Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The latent "factors" influencing spontaneous and clastogen-induced genetic damage, measured by rates of sister chromatid exchange (SCE) and chromosome breakage (CB), were investigated in a small sample of 20 unrelated, healthy individuals. The covariation of spontaneous and clastogen-induced (bleomycin [BLM], streptonigrin [SN], mitomycin-C [MMC], 4-nitroquinoline-1-oxide [4NQO]) SCEs and CBs was analyzed by maximum-likelihood factor analysis. A single-factor model resulted in large standardized regression coefficients of measured variables on the factor for spontaneous and BLM- and SN-induced SCE frequencies, and a modest regression coefficient for MMC-induced SCEs. A two-factor model, after varimax rotation, yielded one factor strongly associated with spontaneous and BLM- and SN-induced SCE frequencies, and a second factor associated with spontaneous and BLM- and SN-induced CBs. A bootstrap analysis of this data set indicated the statistical significance of one regression coefficient (i.e., P less than or equal to 0.05) and borderline significance (0.07 less than or equal to P less than or equal to 0.11) of three other regression coefficients on the first factor, to be interpreted as an effector of SCE frequencies. However, for the second factor, none of the bootstrapped regression coefficients was significant (P greater than 0.22). Due to the modest sample utilized in this study, the validity of this model should be further explored using additional, larger data sets.
Environ Mol Mutagen 1990
PMID:Factors underlying variation in spontaneous and clastogen-induced sister chromatid exchanges and chromosome breakage frequencies. 170 84

Pharmacokinetics, subcellular distribution (SCD), and covalent binding of a single dose of 1 microCi of [S-methyl-3H]bleomycin ([3H]-BLM]) in combination with one unit of unlabeled bleomycin were studied in hamsters following intratracheal (IT) injection. The radioactivity decreased from the lung biexponentially with time. The apparent half-time of absorption for the alpha-phase was 1.1 and 17.9 hr for the beta-phase. The plasma disappearance curve of [3H]BLM fits to a two-compartmental model with the apparent half-life removal for the alpha-phase being 1.6 hr and for the beta-phase 116.9 hr. The radioactivity was detected in all studied tissues. The radioactivity from spleen, testicle, liver, fat, RBC, brain, adrenal, and kidney manifested only the alpha-phase of the disappearance curve, while the beta-phase was complicated by redistribution processes. Of the eight tissues, the spleen had the shortest (2.0 hr) and kidney the longest (12.1 hr), and the remaining tissues had half-lives which ranged from 4 to 10 hr. The SCD study revealed that 85 to 95% of the total radioactivity in the lung and liver homogenate was associated with the soluble fraction (SF) at 30 min after treatment, thereafter, the radioactivity from both tissues gradually decreased to 60% of the total at 24 hr. The SF of the lung homogenate had the highest specific radioactivity (SRA) of any of the fractions during the period between 0.5 and 6 hr. The SRA, however, decreased biexponentially and attained a value similar to that of the mitochondrial and microsomal fractions at 12 and 24 hr after treatment. In the case of liver, the SF had the highest, the nuclear the lowest, and mitochondrial and microsomal fractions the same level of SRA at 30 min. Thereafter, the SRA of all fractions were increased with time. A significant amount of radioactivity from [3H]BLM was covalently bound to lung, liver, and plasma proteins. The SF of the lung contained an increasing amount of radioactivity covalently bound after 1.5 hr of [3H]BLM injection and nearly all radioactivity measured in the plasma was covalently bound. It was concluded from the findings of this study that the presence of a major portion of [3H]BLM in the SF of the lung and its covalent linkage with the proteins of this fraction might initiate the complex sequence of events at the metabolic level necessary for the pneumotoxicity.
Exp Mol Pathol 1986 Oct
PMID:Pharmacokinetics, subcellular distribution, and covalent binding of [3H]bleomycin in hamsters after intratracheal administration. 242 61

The sequence specificity of bleomycin A5 and of its light-activated cobalt complex were compared by examining the relative cleavage of each strand of two DNA fragments by either species. Significant differences between the two metallobleomycins were observed. The iron-bleomycin (Fe-BLM) complex cleaved the DNA molecules preferentially at dinucleotides GpT and GpC, whereas the light-activated cobalt-bleomycin complex (Co-BLM) showed a preference for cutting at the dinucleotide GpA in addition to cleavage at every GpT dinucleotide. Further, new sites of preferential cleavage were noted for Co-BLM in regions of the DNA where enhanced reaction with DNAaseI can be observed in the presence of the antibiotic. No differences in the cutting behaviour of the Fe-BLM were evident upon irradiation of the reaction mixture. A reduction in the relative efficiency of cutting at GpC sequences by Co-BLM is responsible for the previously observed diminution of double-strand breaks under conditions of photoactivated cleavage. The results are discussed in terms of the likely production of highly reactive, diffusible cutting elements in the light activated reaction which cause cleavage of the DNA in regions where the antibiotic is not bound.
J Mol Recognit 1989 Apr
PMID:Differences between sites of binding to DNA and strand cleavage for complexes of bleomycin with iron or cobalt. 248 75

BLM induces DNA degradation in living cells. We used CHO cells with maximal chromatin compactness (cells synchronized in metaphase), cells with chromatin decondensed by Na butyrate treatments, and control cells with normal chromatin condensation in order to analyse the correlation between chromatin compactness, DNA sensitivity to BLM, efficiency of repair of BLM-induced DNA lesions, and cell viability. We found that the DNA sensitivity to BLM and the efficiency of DNA repair is inversely correlated with the degree of chromatin coiling. Cells with decondensed chromatin are those showing higher DNA sensitivity to BLM but also those having the best efficiency to mend the damage. Accordingly, these cells show an amount of residual DNA lesions and a curve of growth similar to that of control cells. The situation is just the opposite for metaphase cells. The DNA of these cells is more resistant to BLM, but the damage is poorly repaired. The final result is that BLM induces a higher concentration of residual DNA lesions and a lower viability in metaphase than in control cells. Our results suggest that chromatin structure influences the quantity and reparability of the BLM-induced lesions, producing a higher incidence of double strand break in the DNA of cells with marked chromatin condensation.
Environ Mol Mutagen 1993
PMID:DNA response to bleomycin in mammalian cells with variable degrees of chromatin condensation. 768 76

Mutation of the Bloom's syndrome (BS) gene, BLM, results in genomic instability. As the first step toward positional cloning of the gene, tight linkage of BLM and FES at 15q26.1 was detected by genotyping affected in families in which the parents are cousins, so-called homozygosity mapping. Linkage disequilibrium between BLM and FES was detected in Ashkenazi Jews with BS, confirming the linkage results and supporting the hypothesis that the increased frequency of the BS mutation in the Ashkenazim is due to founder effect. The mutated BLM gene is inherited identical by descent in BS persons whose parents are cousins or Ashkenazi Jewish; in persons whose parents do not share a common ancestor, BLM can be mutant at different positions within the gene. In such persons, crossing-over within BLM can occur to form a functionally wild-type gene capable of correcting the mutant phenotype of BS cells. In half the cases in which such somatic intragenic recombination had occurred, reduction to homozygosity was detectable distal to BLM but not proximal to it. We localized the cross-over points in corrected cells to a 250 kb genomic segment and isolated therefrom a 4437 bp cDNA that encodes a 1417 amino acid protein homologous to the RecQ subfamily of DExH box-containing DNA and RNA helicases. The identification of BLM as a putative DNA helicase provides a new and powerful tool to investigate the primary defect in BS and the function of the BLM gene product in maintaining the integrity of the genome.
Hum Mol Genet 1996
PMID:Molecular genetics of Bloom's syndrome. 887 52

Bloom's syndrome (BS), a human recessive disorder associated with an increased risk of malignancy, arises through mutations in both alleles of the BLM gene, which was recently identified as a member of the RecQ helicase family. BS cells are characterized by an increased rate of sister chromatid exchange (SCE). However, a subpopulation of lymphocytes exhibiting a normal level of SCE is observed in some patients. It has been proposed that reversion to a low-SCE phenotype involves an intragenic crossing over between the paternal and maternal BLM alleles, generating a wild-type allele. In this study we characterize a new BLM mutation in a BS patient leading to the replacement, in the C-terminal region of Blm, of a highly conserved cysteine by a phenylalanine in codon 1036. Moreover, our data show that this patient also inherited a BLM allele carrying a mutation affecting its expression and that a somatic intragenic crossing over was involved in reversion to the low-SCE phenotype. Further, we show that both topoisomerase II alpha mRNA and protein levels are decreased in the high-SCE cells derived from this patient, whereas they are normal in the corresponding low-SCE cells. Altogether, our data led us to propose that besides its putative helicase activity, Blm could be involved in transcription regulation.
Hum Mol Genet 1997 Sep
PMID:Characterization of a new BLM mutation associated with a topoisomerase II alpha defect in a patient with Bloom's syndrome. 928 78

The human BLM gene is a member of the Escherichia coli recQ helicase family, which includes the Saccharomyces cerevisiae SGS1 and human WRN genes. Defects in BLM are responsible for the human disease Bloom's syndrome, which is characterized in part by genomic instability and a high incidence of cancer. Here we describe the cloning of rad12+, which is the fission yeast homolog of BLM and is identical to the recently reported rhq1+ gene. We showed that rad12 null cells are sensitive to DNA damage induced by UV light and gamma radiation, as well as to the DNA synthesis inhibitor hydroxyurea. Overexpression of the wild-type rad12+ gene also leads to sensitivity to these agents and to defects associated with the loss of the S-phase and G2-phase checkpoint control. We showed genetically and biochemically that rad12+ acts upstream from rad9+, one of the fission yeast G2 checkpoint control genes, in regulating exit from the S-phase checkpoint. The physical chromosome segregation defects seen in rad12 null cells combined with the checkpoint regulation defect seen in the rad12+ overproducer implicate rad12+ as a key coupler of chromosomal integrity with cell cycle progression.
Mol Cell Biol 1998 May
PMID:Fission yeast rad12+ regulates cell cycle checkpoint control and is homologous to the Bloom's syndrome disease gene. 956 91

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

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.
 ...
PMID:Association of the Bloom syndrome protein with topoisomerase IIIalpha in somatic and meiotic cells. 1072 66

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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