Oxidative stress biomarkers in four Bloom syndrome (BS) patients and in their parents suggest in vivo redox abnormalities in BS phenotype
Introduction
Bloom syndrome (BS, OMIM #210900) is a very rare autosomal recessive disorder, caused by mutations in the BLM gene encoding the DNA helicase RecQ protein-like-3 and located to 15q26.1 [1], [2]. The clinical BS phenotype is characterized by hypersensitivity to sunlight with facial telangiectasia in butterfly midface pattern, severe growth retardation, immunodeficiency, and very high frequency of malignancies of several cell types and sites [3], [4]. The cytogenetic analysis of BS cells shows multiple non-specific chromosomal breakages with interchanges (mostly between homologous chromosomes), and a marked increase in sister chromatid exchanges (SCE) [5], [6], [7]. The current opinion on BS attributes the disease to defective DNA repair as the BLM protein belongs to the RecQ family of helicases, and has similarity to the Werner syndrome protein (WRN) and to the product of the yeast gene SGS1, suggesting that the proteins play similar roles in metabolism, namely by interacting with topoisomerases [8], [9], [10].
Another line of studies suggested that the BS phenotype might be related to oxidative stress based on redox abnormalities in cultured cells from BS patients [11], [12], [13], [14], [15], [16]. However, to date no report is available, to the best our knowledge, evaluating any in vivo abnormalities in oxidative stress biomarkers in BS patients or BS heterozygotes. The present investigation, as a part of a more extensive study of oxidative stress in some cancer-prone genetic diseases [17], [18], [19], was conducted on four BS patients (two siblings and two unrelated patients) and their six parents (obligate heterozygotes), in the hypothesis that an in vivo prooxidant state may be associated to the BS phenotype.
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Study population
Four patients with BS, one male and three females aged 8 to 20 years (14.0 ± 4.9 years), were enrolled in Naples, Italy (unrelated patients NI and GM) and in Izmir, Turkey (sibling patients MK and AK), whose clinical data are summarized in Table 1. Diagnosis was based on clinical and cytogenetic data [3], [4], [5]. Also enrolled were 6 BS heteroygotes (three parental couples), aged 34 to 49 years (42.2 ± 5.2 years), and a total of 78 unrelated controls that were grouped in two age classes, i.e. 52
Results
The levels of leukocyte 8-OHdG in the four BS patients were increased vs. 40 controls in the same age range (4.8 ± 1.7 vs. 2.5 ± 1.0 mol 8-OHdG × 106/mol dG, p = 0.04) (Table 2). The leukocyte 8-OHdG levels in the six BS heterozygotes were superimposable with the data from 24 controls in the same age range.
The urinary levels of 8-OHdG in the four BS patients displayed a non-significant increase vs. 9 control data (7.0 ± 1.7 vs. 5.2 ± 1.3), whereas the BS heterozygotes failed to display any significant
Discussion
An established consensus relates the BS-associated genetic defect with impaired DNA metabolism, since the defective gene, BLM, encodes the RECQL3 protein, belonging to the RECQ family of helicases, required for the maintenance of genomic stability in organisms ranging from bacteria to humans and including RECQL2 (mutated in Werner syndrome), RECQL4 (mutated in Rothmund-Thomson syndrome), and the yeast proteins Sgslp and Rqh1p [1], [10]. Furthermore, BLM protein has been functionally related to
Acknowledgments
The present study, a part of the EUROS (European Research on Oxidative Stress) Project, was supported by the European Commission, DG XII, contract # BMH4-CT98-3107, and by the Italian Association for Fanconi Anaemia Research (AIRFA). Thanks are due to the Contributors to the EUROS Project, who were as follows: Clinicians contributing to patient and control recruitment: Maria A. Pisanti, Anna Saviano; Sample processing and analyses: Paolo Ciavolino, Francesca Gallucci, Virginia Rossi, Emilia
References (27)
- et al.
The Bloom's syndrome gene product is a 3′–5′ DNA helicase
J. Biol. Chem.
(1997) The syndrome of congenital telangiectatic erythema and stunted growth
J. Pediatr.
(1966)Bloom's syndrome. XX. The first 100 cancers
Cancer Genet. Cytogenet.
(1997)- et al.
Colocalization, physical, and functional interaction between Werner and Bloom syndrome proteins
J. Biol. Chem.
(2002) - et al.
Superoxide dismutase activity and chromosome damage in cultured chromosome instability syndrome cells
Mutat. Res.
(1990) - et al.
Detection of free radical-induced DNA damage with bromodeoxyuridine/Hoechst flow cytometry: implications for Bloom's syndrome
Mutat. Res.
(1990) - et al.
Functional link between BLM defective in Bloom's Syndrome and the Ataxia-telangiectasia-mutated protein
ATM J. Biol. Chem.
(2002) - et al.
Uric acid: functions and determination
Methods Enzymol.
(1984) - et al.
Glutathione levels in blood from Ataxia Telangiectasia patients suggest in vivo adaptive mechanisms to oxidative stress
Clin. Biochem.
(2007) - et al.
Molecular genetics of Bloom's syndrome
Hum. Mol. Genet.
(1996)
Bloom's syndrome. III. Analysis of the chromosome aberration characteristic of this disorder
Chromosoma
A manyfold increase in sister chromatid exchanges in Bloom's syndrome lymphocytes
Proc. Natl. Acad. Sci. U. S. A.
Bloom's syndrome. IV. Sister chromatid exchanges in lymphocytes
Am. J. Hum. Genet.
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2020, Annual Reports in Medicinal ChemistryCitation Excerpt :This difference has not been explained, but it is interesting that the first study used cells grown in 3.5% oxygen, which is considered to be more physiological than the ambient oxygen levels used in the later studies.107 Given the susceptibility of G4s to the oxidative modification 8-oxoG, which can impact G4 stability and conformation, and can interfere with transcription, along with the facts that there are defects in the repair of oxidatively damaged DNA in WRN and BLM mutant cells and that G4 oxidation has been linked to transcriptional regulation, it would be interesting to explore whether such G4 oxidation might contribute to the different findings.108–112 The exact mechanisms by which G4s regulate transcription are not well understood in most cases, but they can apparently affect RNA polymerase initiation, promoter-proximal pausing and elongation (reviewed by113).
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