Inhibition and enhancement of eukaryotic gene expression by potential non-B DNA sequences

Delić, Jozo; Onclercq, Rosine; Moisan-Coppey, Maïté

doi:10.1016/0006-291x(91)91263-c

Cited by 20 publications

(8 citation statements)

References 35 publications

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“…Generally, CA-repeats are purine-pyrimidine alternating sequences and hence have the potential to assume Z-DNA conformation, a left-handed double-helix structure that is thermodynamically unfavorable compared to B-DNA conformation. Z-DNA conformation has been described as negatively affecting transcriptional activity[36], [43]. Consistently, we showed that GF100472 regulated C3 promoter activity in a length-dependent manner: the longer the CA-repeat, the lower the transcriptional activity.…”

Section: Discussionsupporting

confidence: 84%

Functional Variant in Complement C3 Gene Promoter and Genetic Susceptibility to Temporal Lobe Epilepsy and Febrile Seizures

et al. 2010

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BackgroundHuman mesial temporal lobe epilepsies (MTLE) represent the most frequent form of partial epilepsies and are frequently preceded by febrile seizures (FS) in infancy and early childhood. Genetic associations of several complement genes including its central component C3 with disorders of the central nervous system, and the existence of C3 dysregulation in the epilepsies and in the MTLE particularly, make it the C3 gene a good candidate for human MTLE.Methodology/Principal FindingsA case-control association study of the C3 gene was performed in a first series of 122 patients with MTLE and 196 controls. Four haplotypes (HAP1 to 4) comprising GF100472, a newly discovered dinucleotide repeat polymorphism [(CA)8 to (CA)15] in the C3 promoter region showed significant association after Bonferroni correction, in the subgroup of MTLE patients having a personal history of FS (MTLE-FS+). Replication analysis in independent patients and controls confirmed that the rare HAP4 haplotype comprising the minimal length allele of GF100472 [(CA)8], protected against MTLE-FS+. A fifth haplotype (HAP5) with medium-size (CA)11 allele of GF100472 displayed four times higher frequency in controls than in the first cohort of MTLE-FS+ and showed a protective effect against FS through a high statistical significance in an independent population of 97 pure FS. Consistently, (CA)11 allele by its own protected against pure FS in a second group of 148 FS patients. Reporter gene assays showed that GF100472 significantly influenced C3 promoter activity (the higher the number of repeats, the lower the transcriptional activity). Taken together, the consistent genetic data and the functional analysis presented here indicate that a newly-identified and functional polymorphism in the promoter of the complement C3 gene might participate in the genetic susceptibility to human MTLE with a history of FS, and to pure FS.Conclusions/SignificanceThe present study provides important data suggesting for the first time the involvement of the complement system in the genetic susceptibility to epileptic seizures and to epilepsy.

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Section: Discussionsupporting

confidence: 84%

Functional Variant in Complement C3 Gene Promoter and Genetic Susceptibility to Temporal Lobe Epilepsy and Febrile Seizures

et al. 2010

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“…The existence of proteins whose interaction with DNA is based on conformation ± but not sequence-speci®c ± recognition has been documented (Bianchi et al, 1988;Herbert et al, 1993;Leith and Russel, 1993;Pearson et al, 1995;Solaro et al, 1995). Transcriptional regulation of many genes involves conformational changes in DNA (Delic et al, 1991;Hanke et al, 1995;Iyer and Struhl, 1995;Spiro et al, 1995;Michelotti et al, 1996), and binding of some transcription factors depends on the conformation of DNA within or adjacent to their binding sites (Grigoriev et al, 1992;Spiro et al, 1993;Hu et al, 1994;May®eld and Miller, 1994). At the level of the p53 protein, modi®cations of the p53 carboxy-terminal regulatory domain either by posttranslational modifications, alternative splicing (Kulesz-Martin et al, 1994;Flaman et al, 1996), or by binding of proteins mimicking the e ect of PAb421 binding would provide another level for determining the speci®city for transactivation of the ever growing list of potential p53 target genes.…”

Section: Discussionmentioning

confidence: 99%

DNA-conformation is an important determinant of sequence-specific DNA binding by tumor suppressor p53

1997

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Sequence-speci®c transactivation of target genes is one of the most important molecular properties of the tumor suppressor p53. Binding of p53 to its target DNAs is tightly regulated, with modi®cations in the carboxyterminal regulatory domain of the p53 protein playing an important role. In this study we examined the possible in¯uence of DNA structure on sequence-speci®c DNA binding by p53, by analysing its binding to p53 consensus elements adopting di erent conformations. We found that p53 has the ability to bind to consensus elements which are present in a double-helical form, as well as to consensus elements which are located within alternative non-B-DNA structures. The ability of a consensus element to adopt either one of these conformations is dependent on its sequence symmetry, and is strongly in¯uenced by its sequence environment. Our data suggest a model according to which the conformational status of the target DNA is an important determinant for sequence-speci®c DNA binding by p53. Modi®cations in the carboxy-terminal regulatory region of p53 possibly determine the preference of p53 for a given DNA conformation.

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“…Large individual differences in the ability to modulate the quantitative level of HMOX-1 activity in response to a given stimulus have been described, which correlate with differences in the length of a microsatellite (GT)n repeat in the 5′ flanking region of the HMOX-1 gene (Exner et al 2004; Hirai et al 2003; Yamada et al 2000). The purine–pyrimidine alternating sequence in the (GT)n repeat has the potential to assume Z-DNA conformation, a left-handed double-helix structure that is thermodynamically unfavorable compared with B-DNA conformation (Rich et al 1984) and has been described as negatively affecting transcriptional activity (Delic et al 1991; Naylor and Clark 1990). Yamada and co-workers demonstrated by transient-transfection assay in cultured cell lines that the larger the number of (GT)n repeats in the HMOX-1 gene promoter, the lower is the HMOX-1 inducibility by ROS (Yamada et al 2000).…”

Section: Discussionmentioning

confidence: 99%

Particulate Air Pollution, Oxidative Stress Genes, and Heart Rate Variability in an Elderly Cohort

Chahine¹,

Baccarelli

Litonjua

et al. 2007

Environ Health Perspect

157

120

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Background and objectivesWe have previously shown that reduced defenses against oxidative stress due to glutathione S-transferase M1 (GSTM1) deletion modify the effects of PM2.5 (fine-particulate air pollution of < 2.5 μm in aerodynamic diameter) on heart rate variability (HRV) in a cross-sectional analysis of the Normative Aging Study, an elderly cohort. We have extended this to include a longitudinal analysis with more subjects and examination of the GT short tandem repeat polymorphism in the heme oxygenase-1 (HMOX-1) promoter.MethodsHRV measurements were taken on 539 subjects. Linear mixed effects models were fit for the logarithm of HRV metrics—including standard deviation of normal-to-normal intervals (SDNN), high frequency (HF), and low frequency (LF)—and PM2.5 concentrations in the 48 hr preceding HRV measurement, controlling for confounders and a random subject effect.ResultsPM2.5 was significantly associated with SDNN (p = 0.04) and HF (p = 0.03) in all subjects. There was no association in subjects with GSTM1, whereas there was a significant association with SDNN, HF, and LF in subjects with the deletion. Similarly, there was no association with any HRV measure in subjects with the short repeat variant of HMOX-1, and significant associations in subjects with any long repeat. We found a significant three-way interaction of PM2.5 with GSTM1 and HMOX-1 determining SDNN (p = 0.008), HF (p = 0.01) and LF (p = 0.04). In subjects with the GSTM1 deletion and the HMOX-1 long repeat, SDNN decreased by 13% [95% confidence interval (CI), −21% to −4%], HF decreased by 28% (95% CI, −43% to −9%), and LF decreased by 20% (95% CI, −35% to −3%) per 10 μg/m3 increase in PM.ConclusionsOxidative stress is an important pathway for the autonomic effects of particles.

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Inhibition and enhancement of eukaryotic gene expression by potential non-B DNA sequences

Cited by 20 publications

References 35 publications

Functional Variant in Complement C3 Gene Promoter and Genetic Susceptibility to Temporal Lobe Epilepsy and Febrile Seizures

Functional Variant in Complement C3 Gene Promoter and Genetic Susceptibility to Temporal Lobe Epilepsy and Febrile Seizures

DNA-conformation is an important determinant of sequence-specific DNA binding by tumor suppressor p53

Particulate Air Pollution, Oxidative Stress Genes, and Heart Rate Variability in an Elderly Cohort

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