Neither age nor sex influence the expression of folate sensitive common fragile sites on human chromosomes

Smeets, Dominique; Merkx, G.F.M.

doi:10.1007/bf00205178

Cited by 10 publications

(3 citation statements)

References 15 publications

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“…observed gaps/breaks. [49][50][51][52] The observed incidence of the fragile site at 6p21 varies from 11% 53 up to 94% 54 in the human population. The nonrandom breakage at 13q22 has been observed by independent laboratories 48,55 and has been proposed to be caused by a new aphidicolin inducible common fragile site.…”

Section: Discussionmentioning

confidence: 99%

Cloning of genetically tagged chromosome break sequences reveals new fragile sites at 6p21 and 13q22

Fechter

Buettel

Kuehnel

et al. 2007

Intl Journal of Cancer

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Fragile sites are specific genomic loci that are especially prone to chromosome breakage. For the human genome there are 31 rare fragile sites and 88 common fragile sites listed in the National Center for Biotechnology Information database; however, the exact number remains unknown. In this study, unstable DNA sequences, which have been previously tagged with a marker gene, were cloned and provided starting points for the characterization of two aphidicolin inducible common fragile sites. Mapping of these unstable regions with six-color fluorescence in situ hybridization revealed two new fragile sites at 6p21 and 13q22, which encompass genomic regions of 9.3 and 3.1 Mb, respectively. According to the fragile site nomenclature they were consequently entitled as FRA6H and FRA13E. Both identified regions are known to be associated with recurrent aberrations in malignant and nonmalignant disorders. It is conceivable that these fragile sites result in genetic damage that might contribute to cancer phenotypes such as osteosarcoma, breast and prostate cancer. ' 2007 Wiley-Liss, Inc.Key words: fragile site; FRA6H; FRA13E; genomic instability; chromosome rearrangements Fragile sites are specific genomic loci that are especially prone to express genomic instability. They can be visualized as gaps and breaks on metaphase chromosomes after culturing cells under conditions of replication stress. Based on their incidence in the human population, they are divided into rare fragile sites, occurring in less than 5% of all individuals, and common fragile sites being a constitutive feature of the genome of probably all individuals. 1According to the National Center for Biotechnology Information (NCBI), there are 31 rare fragile sites and 88 common fragile sites in the human genome. However, the exact number of fragile sites remains unclear, since there are no stringent criteria for inclusion and there is no regular update of the database. 2The molecular basis for the expression of rare fragile sites is the dynamic mutation of expanding CGG trinucleotide or AT-rich minisatellite sequences that after reaching a certain threshold expansion account for the observed instability. [3][4][5][6] In contrast, the molecular basis for breakage of common fragile sites is still unclear. 12 However, analysis of the identified sequences did not reveal any particular sequence structure; an ATrichness and an enrichment of DNA flexibility structures seem to be the only shared features.13,14 It has been hypothesized that the AT-richness leads to an accumulation of DNA secondary structures, which might cause a delayed replication at fragile sites. [15][16][17][18] This perturbed replication at fragile sites was shown to activate cell cycle checkpoints in an ATR-dependent manner. 19 In line with this, several targets and modifiers of the ATR-pathway, such as BRCA1, SMC1, CHK1 and the Fanconi anemia pathway proteins, were reported to be involved in maintenance of fragile sites stability. [20][21][22][23] The replication perturbation may result in doubl...

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Section: Discussionmentioning

confidence: 99%

Cloning of genetically tagged chromosome break sequences reveals new fragile sites at 6p21 and 13q22

Fechter

Buettel

Kuehnel

et al. 2007

Intl Journal of Cancer

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“…The present study used a much larger sample size for more reliable conclusions (12 males and 20 ewes). The results of investigations in human chromosomes from 82 healthy males and females however, revealed nonsignificant variation in the total number of lesions induced by FUdR (Smeets and Merkx, 1990). The findings in two groups of dogs were also shown to be non-significant (Stone et al, 1991a).…”

Section: Gender Variation In Fragile Site Expressionmentioning

confidence: 83%

Induction of Folate Sensitive Chromosomal Fragile Sites by Fudr in Pakistani Lohi Sheep (Ovis aries)

Ali¹,

Babar²,

Abdullah³

2008

Asian Australas. J. Anim. Sci

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An investigation to determine frequency and distribution of folate sensitive chromosomal fragile sites was carried out in a Pakistani breed of Lohi sheep to uncover fragile site phenomena. The means and standard errors of aberrant cell count (AC) and Number of aberrations (NoA) in Lohi sheep were 0.56±0.15 and 0.59±0.16 in the control cultures. FUdR treated cells showed significantly higher (p<0.001) AC and NoA means (2.18±0.33 and 2.65±0.50). The sex comparison for the frequency of expression indicated that males had significantly higher number of aberrant cells and total number of aberrations in FUdR cultures than the female group in Lohi sheep. The comparison of control cultures was however, not significantly different between the two groups. The regression analysis of FUdR-induced chromosomal fragility data analysis of the fragility data predicted very low β of 0.325 and 0.412 for AC and NoA respectively. Lohi chromosomes expressed lesions in only 7 and 24 bands in the control and FUdR cultures respectively. The total number of significantly fragile bands in the Lohi genome was only 4. The X-chromosome of the Lohi sheep was highly stable at 5 μg/ml FUdR with no fragile sites. The sex comparison for the distribution of fragile sites across the Lohi genome did not reveal any noticeable differences.

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“…Confirmation of increased aphidicolin-induced FS expression in TS needs to take into account the large number of conditions which may influence chromosome breakage [Craig-Holmes et al, 1987;Chudley et al, 1990;Smeets and Merkx, 1990;Tedeschi et al, 19921, including tissue specificity of FS expression [Morgan et al, 1988;Murano et al, 19891, culture conditions such as ethanol concentration [Kuwano and Kajii, 19871, menstrual stage cycle in females [Furuya et al, 19911, and knowledge of the population background with regard to common aphidicolin-induced FS [Rao et al, 19881. Although our study could be criticized for not adequately evaluating the role of such variables, the differences between TS and control individuals were consistently different to such a marked degree that it was considered worthwhile to open this avenue of research to the widest possible scrutiny.…”

Section: Discussionmentioning

confidence: 99%

Increased expression of aphidicolin-induced common fragile sites in Tourette syndrome: The key to understand the genetics of comorbid phenotypes?

et al. 1996

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In a comparison of 80 common aphidicolin‐induced fragile sites (FS) between 26 DSM‐IV Tourette syndrome (TS) and 24 control individuals, the mean of the summed break frequencies following mild aphidicolin pre‐treatment was significantly higher in TS individuals than in controls (P <0.001). Other breakpoints encountered during this study, i.e., random breaks, breaks corresponding to rare FS, and breakpoints recorded by others but not listed as common FS according to the Chromosome Coordinating Meeting [1992] were listed as category II breakpoints. By using the most significantly different mean FS breakage figures between TS and control individuals, further stepwise discriminant analysis allowed identification of TS individuals from only a few sites in both the common FS and category II breakpoint groups. Future research needs to focus on confirmation of altered common fragile site expression in association with behavioral variation, whether expression of certain discriminatory sites concurs with specific comorbid disorder expression; the nature of the molecular alterations at these FS and the implications of a genomic instability phenotype for the mapping of a primary TS gene or genes. © 1996 Wiley‐Liss, Inc.

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Neither age nor sex influence the expression of folate sensitive common fragile sites on human chromosomes

Cited by 10 publications

References 15 publications

Cloning of genetically tagged chromosome break sequences reveals new fragile sites at 6p21 and 13q22

Cloning of genetically tagged chromosome break sequences reveals new fragile sites at 6p21 and 13q22

Induction of Folate Sensitive Chromosomal Fragile Sites by Fudr in Pakistani Lohi Sheep (Ovis aries)

Increased expression of aphidicolin-induced common fragile sites in Tourette syndrome: The key to understand the genetics of comorbid phenotypes?

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