Replication dynamics at common fragile site FRA6E

Palumbo, Elisa; Matricardi, Laura; Tosoni, Elena; Bensimon, Aaron; Russo, Antonella

doi:10.1007/s00412-010-0279-4

Cited by 64 publications

(69 citation statements)

References 51 publications

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“…Delayed replication has been considered to be a key molecular feature associated with aCFS expression (Arlt et al 2006;Palumbo et al 2010). However, we found G-negative banding to be the dominant predictor of fragility in our aCFS vs. NFR model, and initial studies examining G vs. R banding patterns and S-phase replication timing showed that G-negative bands are replicated early in S phase (Holmquist et al 1982).…”

Section: Replication Timingmentioning

confidence: 99%

A genome-wide analysis of common fragile sites: What features determine chromosomal instability in the human genome?

et al. 2012

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Chromosomal common fragile sites (CFSs) are unstable genomic regions that break under replication stress and are involved in structural variation. They frequently are sites of chromosomal rearrangements in cancer and of viral integration. However, CFSs are undercharacterized at the molecular level and thus difficult to predict computationally. Newly available genome-wide profiling studies provide us with an unprecedented opportunity to associate CFSs with features of their local genomic contexts. Here, we contrasted the genomic landscape of cytogenetically defined aphidicolin-induced CFSs (aCFSs) to that of nonfragile sites, using multiple logistic regression. We also analyzed aCFS breakage frequencies as a function of their genomic landscape, using standard multiple regression. We show that local genomic features are effective predictors both of regions harboring aCFSs (explaining ∼81% of the deviance in logistic regression models) and of aCFS breakage frequencies (explaining ∼45% of the variance in standard regression models). In our optimal models (based on a combination of biological interpretability and high R-squared value), aCFSs are predominantly located in G-negative chromosomal bands and away from centromeres, are enriched in Alu repeats, and have high DNA flexibility. In alternative models, CpG island density, H3K4me1 coverage, and mononucleotide microsatellite coverage are significant predictors. Also, aCFSs have high fragility when colocated with evolutionarily conserved chromosomal breakpoints. Our models are predictive of the fragility of aCFSs mapped at a higher resolution. Importantly, the genomic features we identified here as significant predictors of fragility allow us to draw valuable inferences on the molecular mechanisms underlying aCFSs.

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Section: Replication Timingmentioning

confidence: 99%

A genome-wide analysis of common fragile sites: What features determine chromosomal instability in the human genome?

et al. 2012

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“…The PARK2 gene is located within a known chromosomal fragile site (FRA6E) and consequently, rearrangements of PARK2 are expected to be frequent in cancer cells (19)(20)(21). Furthermore, Clark and colleagues mate-paired sequenced the genome of the U87MG cell line and found an intrachromosomal translocation within the PARK2 gene (22).…”

Section: Parkin-expressing Glioma Cells Exhibit Delayed Entry Into MImentioning

confidence: 99%

Parkin Pathway Activation Mitigates Glioma Cell Proliferation and Predicts Patient Survival

Yeo

Chai

et al. 2012

Cancer Research

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Mutations in the parkin gene, which encodes a ubiquitin ligase, are a major genetic cause of parkinsonism. Interestingly, parkin also plays a role in cancer as a putative tumor suppressor, and the gene is frequently targeted by deletion and inactivation in human malignant tumors. Here, we investigated a potential tumor suppressor role for parkin in gliomas. We found that parkin expression was dramatically reduced in glioma cells. Restoration of parkin expression promoted G 1 phase cell-cycle arrest and mitigated the proliferation rate of glioma cells in vitro and in vivo. Notably, parkin-expressing glioma cells showed a reduction in levels of cyclin D1, but not cyclin E, and a selective downregulation of Akt serine-473 phosphorylation and VEGF receptor levels. In accordance, cells derived from a parkin-null mouse model exhibited increased levels of cyclin D1, VEGF receptor, and Akt phosphorylation, and divided significantly faster when compared with wild-type cells, with suppression of these changes following parkin reintroduction. Clinically, analysis of parkin pathway activation was predictive for the survival outcome of patients with glioma. Taken together, our study provides mechanistic insight into the tumor suppressor function of parkin in brain tumors and suggests that measurement of parkin pathway activation may be used clinically as a prognostic tool in patients with brain tumor. Cancer Res; 72(10); 2543-53. Ó2012 AACR.

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“…By molecular cytogenetics (Fig. 3A-3C), we excluded the presence of large genomic rearrangements, deletions, or duplications in R311K-p63 OMESCs [15,16]. The resolution of the analysis on DNA extended fibers (molecular combing; Fig.…”

Section: Resultsmentioning

confidence: 99%

Personalized Stem Cell Therapy to Correct Corneal Defects Due to a Unique Homozygous-Heterozygous Mosaicism of Ectrodactyly-Ectodermal Dysplasia-Clefting Syndrome

Barbaro

Nasti

Raffa

et al. 2016

Stem Cells Translational Medicine

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Ectrodactyly-ectodermal dysplasia-clefting (EEC) syndrome is a rare autosomal dominant disease caused by mutations in the p63 gene. To date, approximately 40 different p63 mutations have been identified, all heterozygous. No definitive treatments are available to counteract and resolve the progressive corneal degeneration due to a premature aging of limbal epithelial stem cells. Here, we describe a unique case of a young female patient, aged 18 years, with EEC and corneal dysfunction, who was, surprisingly, homozygous for a novel and de novo R311K missense mutation in the p63 gene. A detailed analysis of the degree of somatic mosaicism in leukocytes from peripheral blood and oral mucosal epithelial stem cells (OMESCs) from biopsies of buccal mucosa showed that approximately 80% were homozygous mutant cells and 20% were heterozygous. Cytogenetic and molecular analyses excluded genomic alterations, thus suggesting a de novo mutation followed by an allelic gene conversion of the wild-type allele by de novo mutant allele as a possible mechanism to explain the homozygous condition. R311K-p63 OMESCs were expanded in vitro and heterozygous holoclones selected following clonal analysis. These R311K-p63 OMESCs were able to generate well-organized and stratified epithelia in vitro, resembling the features of healthy tissues. This study supports the rationale for the development of cultured autologous oral mucosal epithelial stem cell sheets obtained by selected heterozygous R311K-p63 stem cells, as an effective and personalized therapy for reconstructing the ocular surface of this unique case of EEC syndrome, thus bypassing gene therapy approaches. STEM CELLS

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Replication dynamics at common fragile site FRA6E

Cited by 64 publications

References 51 publications

A genome-wide analysis of common fragile sites: What features determine chromosomal instability in the human genome?

A genome-wide analysis of common fragile sites: What features determine chromosomal instability in the human genome?

Parkin Pathway Activation Mitigates Glioma Cell Proliferation and Predicts Patient Survival

Personalized Stem Cell Therapy to Correct Corneal Defects Due to a Unique Homozygous-Heterozygous Mosaicism of Ectrodactyly-Ectodermal Dysplasia-Clefting Syndrome

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