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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

In this study, a sensitive host cell reactivation (HCR) technique was used to examine the repair capacity for DNA damaged by sunlamp exposure in fibroblast strains derived from 5 normal individuals and 8 patients representing three different diseases associated with DNA repair deficiencies. Adenovirus type 2 (Ad 2) was exposed to radiation from a GE 275 W sunlamp and subsequently used to infect fibroblast monolayers. At 48 hr after infection, cells were scored for the presence of viral structural antigens (Vag) using indirect immunofluorescent staining. Previous reports using this technique showed a substantial reduction in the HCR of sunlamp-exposed Ad 2 for infection of excision repair deficient fibroblasts from patients with xeroderma pigmentosum. In contrast, the HCR of Vag synthesis for sunlamp-exposed Ad 2 was in the normal range for the three ataxia telangiectasia, three Bloom's syndrome, and two Huntington's disease fibroblasts strains.
Environ Mol Mutagen 1991
PMID:Host cell reactivation of sunlamp-exposed adenovirus in fibroblasts from patients with Bloom's syndrome, ataxia telangiectasia, and Huntington's disease. 182 56

Compaction, occurring at the eight-cell stage of mouse development, is the process of cell flattening and polarisation by which cellular asymmetry is first established. Changes in the pattern of protein phosphorylation have been correlated with this early event of development (TL Bloom, J McConnell: Mol Reprod Dev 26:199-210, 1990). In the study reported here, groups of embryos were treated in ways known to affect particular features of compaction and were then labeled with [32P]orthophosphate; the phosphoproteins obtained were examined following electrophoresis in one and two dimensions. Four-cell embryos were treated with protein synthesis inhibitors, which advance cell flattening. This treatment resulted in only minor differences from the phosphoprotein profile of untreated four-cell embryos. Inhibition of protein synthesis at the eight-cell stage has little effect on cell flattening or polarisation. However, some phosphoproteins that are observed normally in eight-cell but not in four-cell embryos were no longer detectable if labeling took place in the presence of protein synthesis inhibitors. Eight-cell embryos incubated in phorbol 12-myristate 13-acetate, which disrupts various features of compaction, showed a relative increase in the phosphorylation of a group of phosphoprotein spots associated with the eight-cell but not with the four-cell stage. Embryos incubated in Ca2(+)-free medium, which prevents intercellular flattening and delays polarisation, showed a relative decrease in the phosphorylation of the same group of phosphoprotein spots. The behaviour of these phosphoproteins may therefore be correlated with some of the features of compaction.
Mol Reprod Dev 1991 Mar
PMID:Experimental manipulation of compaction of the mouse embryo alters patterns of protein phosphorylation. 201 81

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

Human hereditary diseases such as xeroderma pigmentosum, Fanconi's anemia, ataxia telangiectasia, and Bloom's syndrome are characterized by a proneness for developing cancer associated with abnormalities in the processing of DNA damage. The molecular defects responsible for predisposing human tissues to cancer are still not well understood, despite the fact that a considerable amount of work has already been done on this problem. In this paper, we show that in human tumor cell lines, in cells transformed by DNA tumor viruses, and in cells derived from certain cancer-prone disorders, the level of activity of a 42-kDa deoxyribonuclease is many times higher than in diploid untransformed control cells. This suggests that this activity is linked to, or may play a role in, malignant transformation.
Mol Carcinog 1989
PMID:Enhanced deoxyribonuclease activity in human transformed cells and in Bloom's syndrome cells. 280 19

The effects of Bloom's syndrome (BS) fibroblasts on genetic recombination and the mutation frequency of herpes simplex virus type 1 (HSV-1) was determined by employing two factor crosses of selected temperature-sensitive (ts) mutants. A significant increase in the recombination frequency (RF) was observed in seven of nine crosses when multiple BS fibroblast lines were compared to normal human fibroblasts. The RF of HSV-1 ts mutants increased following 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment of normal, but not BS fibroblasts, suggesting that BS fibroblasts express higher constitutive levels of genetic recombination activity. HSV-1 ts mutants demonstrated significantly higher reversion frequencies to the nontemperature sensitive (ts+) phenotype following growth in BS rather than normal fibroblasts, indicating that exogenous viral DNA encoding many of the enzymes necessary for its own replication is affected by the mutator phenotype of BS.
Somat Cell Mol Genet 1987 Mar
PMID:Effects of Bloom's syndrome fibroblasts on genetic recombination and mutagenesis of herpes simplex virus type 1. 303 25

The Chinese hamster cell line mutant EM9, which has a reduced ability to repair DNA strand breaks, is noted for its highly elevated frequency of sister chromatid exchange, a property shared with cells from individuals with Bloom's syndrome. The defect in EM9 cells was corrected by fusion hybridization with normal human fibroblasts and by transfection with DNA from hybrid cells. The transformants showed normalization of sister chromatid exchange frequency but incomplete correction of the repair defect in terms of chromosomal aberrations produced by 5-bromo-2'-deoxyuridine.
Mol Cell Biol 1985 Apr
PMID:DNA-mediated transfer of a human DNA repair gene that controls sister chromatid exchange. 399 Jun 94

Three biochemically distinct DNA ligase activities have been identified in mammalian cell extracts. We have recently purified DNA ligase II and DNA ligase III to near homogeneity from bovine liver and testis tissue, respectively. Amino acid sequencing studies indicated that these enzymes are encoded by the same gene. In the present study, human and murine cDNA clones encoding DNA ligase III were isolated with probes based on the peptide sequences. The human DNA ligase III cDNA encodes a polypeptide of 862 amino acids, whose sequence is more closely related to those of the DNA ligases encoded by poxviruses than to replicative DNA ligases, such as human DNA ligase I. In vitro transcription and translation of the cDNA produced a catalytically active DNA ligase similar in size and substrate specificity to the purified bovine enzyme. The DNA ligase III gene was localized to human chromosome 17, which eliminated this gene as a candidate for the cancer-prone disease Bloom syndrome that is associated with DNA joining abnormalities. DNA ligase III is ubiquitously expressed at low levels, except in the testes, in which the steady-state levels of DNA ligase III mRNA are at least 10-fold higher than those detected in other tissues and cells. Since DNA ligase I mRNA is also present at high levels in the testes, we examined the expression of the DNA ligase genes during spermatogenesis. DNA ligase I mRNA expression correlated with the contribution of proliferating spermatogonia cells to the testes, in agreement with the previously defined role of this enzyme in DNA replication. In contrast, elevated levels of DNA ligase III mRNA were observed in primary spermatocytes undergoing recombination prior to the first meiotic division. Therefore, we suggest that DNA ligase III seals DNA strand breaks that arise during the process of meiotic recombination in germ cells and as a consequence of DNA damage in somatic cells.
Mol Cell Biol 1995 Oct
PMID:Mammalian DNA ligase III: molecular cloning, chromosomal localization, and expression in spermatocytes undergoing meiotic recombination. 756 92

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


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