scholarly journals The transcriptionally competent U2 gene is necessary and sufficient for adenovirus type 12 induction of the fragile site at 17q21-22.

1995 ◽  
Vol 15 (11) ◽  
pp. 6256-6261 ◽  
Author(s):  
S Gargano ◽  
P Wang ◽  
E Rusanganwa ◽  
S Bacchetti
Keyword(s):  
Human Genome ◽  
Tandem Repeats ◽  
Fragile Site ◽  
Adenovirus Type ◽  
Fragile Sites ◽  
Human Cells ◽  
Necessary And Sufficient

Adenovirus type 12 induces four fragile sites upon infection of human cells. The U2 locus, consisting of up to 20 tandem repeats of a 5.8-kbp monomer, maps at the most sensitive of these sites at 17q21-22. We have previously shown that an artificial U2 locus integrated into the human genome generates a new virus-induced fragile site. To determine which elements within the U2 monomer are responsible for fragility, we constructed loci consisting of tandem repeats of subfragments of the U2 monomer. With this approach, we demonstrate that a transcriptionally competent U2 gene is necessary and sufficient for virus-induced fragility and that no other element within the 5.8-kbp monomer contributes to this effect.

Generation of a new adenovirus type 12-inducible fragile site by insertion of an artificial U2 locus in the human genome

1993 ◽  
Vol 13 (10) ◽  
pp. 6064-6070
Author(s):  
Y P Li ◽  
R Tomanin ◽  
J R Smiley ◽  
S Bacchetti
Keyword(s):  
Human Genome ◽  
Gene Cluster ◽  
Fragile Site ◽  
Adenovirus Type ◽  
Fragile Sites ◽  
Human Cells ◽  
Major Site ◽  
Chromosome 13 ◽  
Direct Assessment

Infection with adenovirus type 12 (Ad12) induces four fragile sites in the human genome (H.F. Stich, G.L. van Hoosier, and J.J. Trentin, Exp. Cell Res. 34:400-403, 1964; H. zur Hausen, J. Virol. 1:1174-1185, 1967). The major site, at 17q21-22, contains the U2 gene cluster, which is specifically disrupted by infection in at least a percentage of the cells (D.M. Durnam, J.C. Menninger, S.H. Chandler, P.P. Smith, and J.K. McDougall, Mol. Cell. Biol. 8:1863-1867, 1988). For direct assessment of whether the U2 locus is the target of the Ad12 effect, an artificial locus, constructed in vitro and consisting of tandem arrays of the U2 6-kbp monomer, was transfected into human cells. We report that integration of this artificial locus on the p arm of chromosome 13 creates a new Ad12-inducible fragile site.

scholarly journals Generation of a new adenovirus type 12-inducible fragile site by insertion of an artificial U2 locus in the human genome.

1993 ◽  
Vol 13 (10) ◽  
pp. 6064-6070 ◽  
Author(s):  
Y P Li ◽  
R Tomanin ◽  
J R Smiley ◽  
S Bacchetti
Keyword(s):  
Human Genome ◽  
Gene Cluster ◽  
Fragile Site ◽  
Adenovirus Type ◽  
Fragile Sites ◽  
Human Cells ◽  
Major Site ◽  
Chromosome 13 ◽  
Direct Assessment

Infection with adenovirus type 12 (Ad12) induces four fragile sites in the human genome (H.F. Stich, G.L. van Hoosier, and J.J. Trentin, Exp. Cell Res. 34:400-403, 1964; H. zur Hausen, J. Virol. 1:1174-1185, 1967). The major site, at 17q21-22, contains the U2 gene cluster, which is specifically disrupted by infection in at least a percentage of the cells (D.M. Durnam, J.C. Menninger, S.H. Chandler, P.P. Smith, and J.K. McDougall, Mol. Cell. Biol. 8:1863-1867, 1988). For direct assessment of whether the U2 locus is the target of the Ad12 effect, an artificial locus, constructed in vitro and consisting of tandem arrays of the U2 6-kbp monomer, was transfected into human cells. We report that integration of this artificial locus on the p arm of chromosome 13 creates a new Ad12-inducible fragile site.

A fragile site in the human U2 small nuclear RNA gene cluster is revealed by adenovirus type 12 infection

1988 ◽  
Vol 8 (5) ◽  
pp. 1863-1867
Author(s):  
D M Durnam ◽  
J C Menninger ◽  
S H Chandler ◽  
P P Smith ◽  
J K McDougall
Keyword(s):  
Gene Cluster ◽  
Fragile Site ◽  
Maximum Size ◽  
Adenovirus Type ◽  
Fragile Sites ◽  
Similar Data ◽  
Small Nuclear Rna ◽  
Structural Alterations ◽  
Nuclear Rna

Using in situ hybridization, we found that the U2 small nuclear RNA gene cluster mapped very close to and was frequently disrupted by the gaps and breaks induced specifically in the human 17q21-q22 region by highly oncogenic adenovirus type 12 (Ad12). Restriction mapping revealed no structural alterations in the U2 gene locus as a result of Ad12 infection. Likewise, no Ad12-induced alterations in U2 RNA levels were detected. We estimate that the maximum size of the region specifically disrupted by this virus was less than 350 to 700 kilobases. A comparison of these data with similar data regarding biochemically induced fragile sites was made.

scholarly journals A fragile site in the human U2 small nuclear RNA gene cluster is revealed by adenovirus type 12 infection.

1988 ◽  
Vol 8 (5) ◽  
pp. 1863-1867 ◽  
Author(s):  
D M Durnam ◽  
J C Menninger ◽  
S H Chandler ◽  
P P Smith ◽  
J K McDougall
Keyword(s):  
Gene Cluster ◽  
Fragile Site ◽  
Maximum Size ◽  
Adenovirus Type ◽  
Fragile Sites ◽  
Similar Data ◽  
Small Nuclear Rna ◽  
Structural Alterations ◽  
Nuclear Rna

Using in situ hybridization, we found that the U2 small nuclear RNA gene cluster mapped very close to and was frequently disrupted by the gaps and breaks induced specifically in the human 17q21-q22 region by highly oncogenic adenovirus type 12 (Ad12). Restriction mapping revealed no structural alterations in the U2 gene locus as a result of Ad12 infection. Likewise, no Ad12-induced alterations in U2 RNA levels were detected. We estimate that the maximum size of the region specifically disrupted by this virus was less than 350 to 700 kilobases. A comparison of these data with similar data regarding biochemically induced fragile sites was made.

scholarly journals AT-dinucleotide rich sequences drive fragile site formation

2019 ◽  
Vol 47 (18) ◽  
pp. 9685-9695 ◽  
Author(s):  
Michal Irony-Tur Sinai ◽  
Anita Salamon ◽  
Noemie Stanleigh ◽  
Tchelet Goldberg ◽  
Aryeh Weiss ◽  
...  
Keyword(s):  
Dna Replication ◽  
Human Genome ◽  
Dna Sequences ◽  
Fragile Site ◽  
Integration Site ◽  
Replication Stress ◽  
Secondary Structures ◽  
Fragile Sites ◽  
Stable Region ◽  
Site Formation

Abstract Common fragile sites (CFSs) are genomic regions prone to breakage under replication stress conditions recurrently rearranged in cancer. Many CFSs are enriched with AT-dinucleotide rich sequences (AT-DRSs) which have the potential to form stable secondary structures upon unwinding the double helix during DNA replication. These stable structures can potentially perturb DNA replication progression, leading to genomic instability. Using site-specific targeting system, we show that targeted integration of a 3.4 kb AT-DRS derived from the human CFS FRA16C into a chromosomally stable region within the human genome is able to drive fragile site formation under conditions of replication stress. Analysis of >1300 X chromosomes integrated with the 3.4 kb AT-DRS revealed recurrent gaps and breaks at the integration site. DNA sequences derived from the integrated AT-DRS showed in vitro a significantly increased tendency to fold into branched secondary structures, supporting the predicted mechanism of instability. Our findings clearly indicate that intrinsic DNA features, such as complexed repeated sequence motifs, predispose the human genome to chromosomal instability.

scholarly journals FANCD2 modulates the mitochondrial stress response to prevent common fragile site instability

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Philippe Fernandes ◽  
Benoit Miotto ◽  
Claude Saint-Ruf ◽  
Maha Said ◽  
Viviana Barra ◽  
...  
Keyword(s):  
Stress Response ◽  
Genome Instability ◽  
Fragile Site ◽  
Fragile Sites ◽  
Human Cells ◽  
Mitochondrial Stress ◽  
Stress Response Pathway ◽  
Stress Dependent ◽  
Large Genes ◽  
Genomic Regions

AbstractCommon fragile sites (CFSs) are genomic regions frequently involved in cancer-associated rearrangements. Most CFSs lie within large genes, and their instability involves transcription- and replication-dependent mechanisms. Here, we uncover a role for the mitochondrial stress response pathway in the regulation of CFS stability in human cells. We show that FANCD2, a master regulator of CFS stability, dampens the activation of the mitochondrial stress response and prevents mitochondrial dysfunction. Genetic or pharmacological activation of mitochondrial stress signaling induces CFS gene expression and concomitant relocalization to CFSs of FANCD2. FANCD2 attenuates CFS gene transcription and promotes CFS gene stability. Mechanistically, we demonstrate that the mitochondrial stress-dependent induction of CFS genes is mediated by ubiquitin-like protein 5 (UBL5), and that a UBL5-FANCD2 dependent axis regulates the mitochondrial UPR in human cells. We propose that FANCD2 coordinates nuclear and mitochondrial activities to prevent genome instability.

Control of cellular gene expression during adenovirus infection: induction and shut-off of dihydrofolate reductase gene expression by adenovirus type 2

1983 ◽  
Vol 3 (5) ◽  
pp. 819-828 ◽  
Author(s):  
S S Yoder ◽  
B L Robberson ◽  
E J Leys ◽  
A G Hook ◽  
M Al-Ubaidi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Synthesis ◽  
Steady State ◽  
Dihydrofolate Reductase ◽  
Relative Rate ◽  
Single Gene ◽  
Adenovirus Type ◽  
Human Cells ◽  
Adenovirus Infection ◽  
Specific Mrna

Infection of human cells by adenovirus results in multiple alterations of host gene expression. To examine the effects of viral infection on the expression of a single gene, a line of human cells was developed which is resistant to growth in methotrexate and which contains amplified RNA and protein specific for dihydrofolate reductase (DHFR). Cytogenetic evidence indicated the presence of amplified DNA. Adenovirus infection of these cells caused an induction and subsequent decline in the synthesis of DHFR protein. The maximum DHFR induction occurred 16 to 19 h after infection and reached a level 2.5-fold greater than that observed in uninfected cells. Induction of DHFR protein synthesis was accompanied by concomitant increases in the level of steady-state DHFR-specific cytoplasmic RNA. The relative rate of DHFR mRNA production (i.e., the appearance of DHFR-specific mRNA sequences in the cytoplasm) also increased 2.5-fold during induction. Later in infection, the relative rate of DHFR protein synthesis declined, reaching a level below that observed in uninfected cells. This decline was accompanied by a similar decline in the steady-state levels of DHFR RNA and in the relative rate of synthesis of DHFR mRNA. These data suggest that adenovirus infection controls DHFR gene expression by increasing and subsequently decreasing the relative rate at which DHFR-specific mRNA sequences appear in the cytoplasm and enter the pool of mRNA available for translation.

Fragile Sites on Chromosomes

PEDIATRICS ◽  
1982 ◽  
Vol 69 (1) ◽  
pp. 121-123
Author(s):  
Frederick Hecht ◽  
Thomas W. Glover ◽  
Barbara Kaiser-Hecht
Keyword(s):  
Mental Retardation ◽  
X Chromosome ◽  
Fanconi Anemia ◽  
Ataxia Telangiectasia ◽  
Autosomal Recessive ◽  
Fragile Site ◽  
Chromosome Instability ◽  
Chromosome Complement ◽  
Fragile Sites ◽  
Chromosome Fragility

A fragile site on the X chromosome is associated with a common form of mental retardation in males and a proportion of females.1-3 This association was not fully appreciated when the fragile site on the X was first described in 1969,4 but it is crystal-clear today. Chromosome fragility can be random, as in Fanconi anemia, Bloom syndrome, and ataxia-telangiectasia, the chromosome instability syndromes.5 Breaks and rearrangements of chromosomes are seen in these disorders, all of which are autosomal recessive conditions predisposing to cancer. Fragile sites are special spots in the genome where gaps and breaks occur nonrandomly. The balance of the chromosome complement is normal.

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