scholarly journals Replication Delay along FRA7H, a Common Fragile Site on Human Chromosome 7, Leads to Chromosomal Instability

2000 ◽  
Vol 20 (12) ◽  
pp. 4420-4427 ◽  
Author(s):  
Asaf Hellman ◽  
Ayelet Rahat ◽  
Stephen W. Scherer ◽  
Ariel Darvasi ◽  
Lap-Chee Tsui ◽  
...  
Keyword(s):  
Chromosomal Instability ◽  
Fragile Site ◽  
S Phase ◽  
Fragile Sites ◽  
Common Fragile Site ◽  
Replication Pattern ◽  
Replication Time ◽  
The Common ◽  
Human Chromosome 7

ABSTRACT Common fragile sites are specific chromosomal loci that show gaps, breaks, or rearrangements in metaphase chromosomes under conditions that interfere with DNA replication. The mechanism underlying the chromosomal instability at fragile sites was hypothesized to associate with late replication time. Here, we aimed to investigate the replication pattern of the common fragile site FRA7H, encompassing 160 kb on the long arm of human chromosome 7. Using in situ hybridization on interphase nuclei, we revealed that the replication of this region is initiated relatively early, before 30% of S phase is completed. However, a high fraction (∼35%) of S-phase nuclei showed allelic asynchrony, indicating that the replication of FRA7H is accomplished at different times in S phase. This allelic asynchrony is not the result of a specific replication time of each FRA7H allele. Analysis of the replication pattern of adjacent clones along FRA7H by using cell population and two-color fluorescent in situ hybridization analyses showed significant differences in the replication of adjacent clones, under normal growth condition and upon aphidicolin treatment. This pattern significantly differed from that of two nonfragile regions which showed a coordinated replication under both conditions. These results indicate that aphidicolin is enhancing an already existing difference in the replication time along the FRA7H region. Based on our replication analysis of FRA7H and on previous analysis of the common fragile site FRA3B, we suggest that delayed replication is underlying the fragility at aphidicolin-induced common fragile sites.

scholarly journals Translocation t(3;8)(p14.2;q24.1) in renal cell carcinoma affects expression of the common fragile site at 3p14(FRA3B) in lymphocytes

1988 ◽  
Vol 31 (1) ◽  
pp. 69-73 ◽  
Author(s):  
Thomas W. Glover ◽  
Jane F. Coyle-Morris ◽  
Frederick P. Li ◽  
Robert S. Brown ◽  
Carol S. Berger ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Fragile Site ◽  
Common Fragile Site ◽  
The Common

The common fragile site FRA16D and its associated geneWWOX are highly conserved in the mouse at Fra8E1

2002 ◽  
Vol 34 (2) ◽  
pp. 154-167 ◽  
Author(s):  
Kurt A. Krummel ◽  
Stacy R. Denison ◽  
Eric Calhoun ◽  
Leslie A. Phillips ◽  
David I. Smith
Keyword(s):  
Fragile Site ◽  
Common Fragile Site ◽  
The Common

scholarly journals BRCA1 Is Required for Common-Fragile-Site Stability via Its G2/M Checkpoint Function

2004 ◽  
Vol 24 (15) ◽  
pp. 6701-6709 ◽  
Author(s):  
Martin F. Arlt ◽  
Bo Xu ◽  
Sandra G. Durkin ◽  
Anne M. Casper ◽  
Michael B. Kastan ◽  
...  
Keyword(s):  
Rna Interference ◽  
Tumor Suppressor ◽  
Dna Synthesis ◽  
Cancer Cells ◽  
Tumor Suppressor Genes ◽  
Fragile Site ◽  
Fragile Sites ◽  
Common Fragile Site ◽  
Interacting Proteins ◽  
Checkpoint Pathway

ABSTRACT Common fragile sites are loci that form chromosome gaps or breaks when DNA synthesis is partially inhibited. Fragile sites are prone to deletions, translocations, and other rearrangements that can cause the inactivation of associated tumor suppressor genes in cancer cells. It was previously shown that ATR is critical to fragile-site stability and that ATR-deficient cells have greatly elevated fragile-site expression (A. M. Casper, P. Nghiem, M. F. Arlt, and T. W. Glover, Cell 111:779-789, 2002). Here we demonstrate that mouse and human cells deficient for BRCA1, due to mutation or knockdown by RNA interference, also have elevated fragile-site expression. We further show that BRCA1 functions in the induction of the G2/M checkpoint after aphidicolin-induced replication stalling and that this checkpoint function is involved in fragile-site stability. These data indicate that BRCA1 is important in fragile-site stability and that fragile sites are recognized by the G2/M checkpoint pathway, in which BRCA1 plays a key role. Furthermore, they suggest that mutations in BRCA1 or interacting proteins could lead to rearrangements at fragile sites in cancer cells.

Abnormalities of 16q in Multiple Myeloma Are Associated with Poor Prognosis: 500K Gene Mapping and Expression Correlations Identify Two Potential Tumor Suppressor Genes, WWOX and CYLD.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 110-110
Author(s):  
Matthew W. Jenner ◽  
Paola E. Leone ◽  
Brian A. Walker ◽  
David C. Johnson ◽  
Laura Chiecchio ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Gene Mapping ◽  
Tumor Suppressor Genes ◽  
Poor Prognosis ◽  
Fragile Site ◽  
Fragile Sites ◽  
Common Fragile Site ◽  
Chromosome 16 ◽  
Common Fragile Sites ◽  
Potential Tumor Suppressor

Abstract Abnormalities of 16q are important recurrent events in multiple myeloma (MM). We performed FISH on CD138 selected plasma cells from 701 newly diagnosed MM patients from the LRF UKMF cytogenetics database. Gene mapping, including paired normal controls, and gene expression analysis was performed on 55 cases using the Affymetrix Human Mapping 500K Array Set and U133 Plus 2.0 Arrays respectively. 16q deletion (del16q) was identified by FISH using probes for cMAF (Abbott Diagnostics) in 131/701 cases (18.7%) and was significantly associated with deletion 17p (16.5% vs. 8.9%, p=0.006), deletion 13 (60.8% vs. 48.5%, p=0.009), deletion of IgH (22.1% vs. 11.1%, p=0.0003) and non-hyperdiploid status (58.3% vs. 42.7%, p=0.006). Del16q showed a trend to poor overall survival, mean survival 43 vs. 61 months (p=0.09), and was associated with significantly worse survival in combination with t(4;14) compared with either t(4;14) or del16q alone, mean survival 15 vs. 26 vs. 45 months respectively (p=0.006). t(14;16) was identified by FISH in 31/701 cases (4.4%) and was associated with poor prognosis, mean survival 29 vs. 54 months (p=0.005). Mapping arrays revealed loss of heterozygosity (LOH) involving all or part of 16q in 20 of 55 cases (36%) in 3 distinct patterns: uniparental disomy (UPD) of chromosome 16 or 16q in 4/55 cases (7%); deletion of chromosome 16 or the whole of 16q in 11/55 cases (20%); and interstitial deletion of small regions of 16q in 5/55 cases (10%), focused on 16q12, the location of CYLD, and 16q23, the location of WWOX. 16q LOH was distributed across translocation groups but was identified in all 4 mapping cases containing 17p deletion, supporting the association identified by FISH. As WWOX is the site of the common fragile site FRA16D and deletions at common fragile sites have been associated with DNA instability in human cancers, we assessed this using gene mapping in these 55 MM cases. Although deletions spanning other common fragile sites were identified, they were not restricted to those with 16q LOH. However, in 2 t(14;16) cases, hemizygous deletions of approximately 100kb could be identified within WWOX at the presumed translocation breakpoint. One of the t(14;16) cases had a similar hemizygous deletion within FHIT, another tumor suppressor gene located within common fragile site FRA3B, consistent with findings in other cancer types. Cases with 16q LOH or t(14;16) all had significantly reduced WWOX expression relative to cases without 16q abnormalities, confirming gene inactivation by either LOH or translocation. Cases with 16q LOH also had significantly reduced expression of two other potential tumor suppressor genes located on 16q, CYLD and RBL2. In summary, our data confirms the adverse prognosis associated with 16q translocation or deletion. Array data reveals 16q LOH occurs due to deletion or UPD with two regions involved, one defined by CYLD and the other by WWOX. WWOX is also inactivated by translocation and is associated with interstitial deletions at this and other common fragile sites. WWOX is a likely candidate gene in MM pathogenesis because of its interaction with TP53 and CYLD via its effects on NF-κB.

scholarly journals Induction of the common fragile site FRA3B does not affect FHIT expression

Oncogene ◽  
2001 ◽  
Vol 20 (14) ◽  
pp. 1798-1801 ◽  
Author(s):  
Dagmar Michael ◽  
Manfred F Rajewsky
Keyword(s):  
Fragile Site ◽  
Common Fragile Site ◽  
The Common

scholarly journals Human DNA Polymerase η Is Required for Common Fragile Site Stability during Unperturbed DNA Replication

2009 ◽  
Vol 29 (12) ◽  
pp. 3344-3354 ◽  
Author(s):  
Laurie Rey ◽  
Julia M. Sidorova ◽  
Nadine Puget ◽  
François Boudsocq ◽  
Denis S. F. Biard ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Polymerase ◽  
Genome Stability ◽  
Fragile Site ◽  
S Phase ◽  
Human Cells ◽  
Common Fragile Site ◽  
Exogenous Dna ◽  
Human Dna

ABSTRACT Human DNA polymerase η (Pol η) modulates susceptibility to skin cancer by promoting translesion DNA synthesis (TLS) past sunlight-induced cyclobutane pyrimidine dimers. Despite its well-established role in TLS synthesis, the role of Pol η in maintaining genome stability in the absence of external DNA damage has not been well explored. We show here that short hairpin RNA-mediated depletion of Pol η from undamaged human cells affects cell cycle progression and the rate of cell proliferation and results in increased spontaneous chromosome breaks and common fragile site expression with the activation of ATM-mediated DNA damage checkpoint signaling. These phenotypes were also observed in association with modified replication factory dynamics during S phase. In contrast to that seen in Pol η-depleted cells, none of these cellular or karyotypic defects were observed in cells depleted for Pol ι, the closest relative of Pol η. Our results identify a new role for Pol η in maintaining genomic stability during unperturbed S phase and challenge the idea that the sole functional role of Pol η in human cells is in TLS DNA damage tolerance and/or repair pathways following exogenous DNA damage.

scholarly journals Common Fragile Site Profiling in Epithelial and Erythroid Cells Reveals that Most Recurrent Cancer Deletions Lie in Fragile Sites Hosting Large Genes

Cell Reports ◽  
2013 ◽  
Vol 4 (3) ◽  
pp. 420-428 ◽  
Author(s):  
Benoît Le Tallec ◽  
Gaël Armel Millot ◽  
Marion Esther Blin ◽  
Olivier Brison ◽  
Bernard Dutrillaux ◽  
...  
Keyword(s):  
Fragile Site ◽  
Fragile Sites ◽  
Common Fragile Site ◽  
Erythroid Cells ◽  
Recurrent Cancer ◽  
Large Genes
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