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B Boscherini - One of the best experts on this subject based on the ideXlab platform.
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increased Chromosome Fragility in lymphocytes of short normal children treated with recombinant human growth hormone
Human Genetics, 1993Co-Authors: B Tedeschi, Gian Luigi Spadoni, Maria Lucia Sanna, P Vernole, Daniela Caporossi, Stefano Cianfarani, B Nicoletti, B BoscheriniAbstract:A few years ago it was reported that some growth-hormone-deficient children had developed leukemia following therapy with human growth hormone. This raised concern that this therapy may stimulate tumor development. Since it is known that the tendency to develop cancer is closely related to Chromosome breakage, we decided to investigate whether recombinant human growth hormone (rhGH) therapy can increase Chromosome Fragility. Ten short normal children were studied during their first year of treatment. Lymphocytes were collected at 0, 6 and 12 months of rhGH therapy, and we assessed the rate of spontaneous Chromosome aberrations, the frequency of sister chromatid exchanges, the proliferative rate indices, the expression of common fragile sites induced by aphidicolin, and the sensitivity towards the radiomimetic action of bleomycin. At 6 months of therapy, there was a significant increase in bleomycin-induced Chromosome aberrations, which remained unchanged after 1 year of treatment. An increase in spontaneous Chromosome rearrangements at 6 and 12 months of therapy was also observed. These findings are further supported by data obtained from the analysis of 16 short normal children already on rhGH therapy.
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increased Chromosome Fragility in lymphocytes of short normal children treated with recombinant human growth hormone
Pediatric Research, 1993Co-Authors: Gian Luigi Spadoni, B Tedeschi, Maria Lucia Sanna, P Vernole, Daniela Caporossi, Stefano Cianfarani, B Nicoletti, B BoscheriniAbstract:The report, few years ago, of some growth hormone-deficient children having developed leukemia following therapy with human growth hormone, raised concern about a possible stimulatory effect of this therapy on tumor development. Since it is known that proneness to cancer is related to Chromosome breakage, we decided to investigate whether recombinant human growth hormone (rhGH) therapy might increase Chromosome Fragility. Ten short-normal children (age: 6-11 yrs. mean height: −2.5 SD; mean growth rate: 4.1 cm/yr; mean bone age: −2.5 SD) were studied. Lymphocytes were collected at 0, 6 and 12 months of therapy, and the rate of spontaneous Chromosome aberrations, the frequency of sister chromatid exchanges, the proiterative rate indices, the expression of common fragile sites induced by aphidicolin, and the sensitivity towards the radiomimetic action of bleomicin (BLM) were assessed. The mean frequency of BLM-induced Chromosome aberrations increased from the pretherapy 0.11 breaks/cell (b/c) value to 0.23 b/c at 6 months of therapy (p<0.01), and remained at the same level (0.22 b/c) at 12 months. The frequency of damaged cells, showed a significative difference (p<0.05) between the pretherapy value (0.09) and the value found in the cultures performed at 6 and 12 months of therapy (0.14). An increase in spontaneous Chromosome rearrangements at 6 and 12 months of therapy was also observed. These findings are supported by data obtained from the analysis of 16 short normal children already on rhGH therapy. Our data point out the need for rhGH to be given only in the strictest of indications. The opportunity of starting rhGH therapy should be carefully questioned when short stature is associated with conditions at risk for the development of tumours, for an increased chromosomal radiosensitivity, e.g. Down syndrome, or tor increased chromosomal breakage, e.g. Fanconi anemia and Bloom syndrome.
Catherine H Freudenreich - One of the best experts on this subject based on the ideXlab platform.
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the role of fork stalling and dna structures in causing Chromosome Fragility
Genes Chromosomes and Cancer, 2019Co-Authors: Simran Kaushal, Catherine H FreudenreichAbstract:Alternative non-B form DNA structures, also called secondary structures, can form in certain DNA sequences under conditions that produce single-stranded DNA, such as during replication, transcription, and repair. Direct links between secondary structure formation, replication fork stalling, and genomic instability have been found for many repeated DNA sequences that cause disease when they expand. Common fragile sites (CFSs) are known to be AT-rich and break under replication stress, yet the molecular basis for their Fragility is still being investigated. Over the past several years, new evidence has linked both the formation of secondary structures and transcription to fork stalling and Fragility of CFSs. How these two events may synergize to cause Fragility and the role of nuclease cleavage at secondary structures in rare and CFSs are discussed here. We also highlight evidence for a new hypothesis that secondary structures at CFSs not only initiate Fragility but also inhibit healing, resulting in their characteristic appearance.
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differential requirement of srs2 helicase and rad51 displacement activities in replication of hairpin forming cag ctg repeats
Nucleic Acids Research, 2017Co-Authors: Jennifer H.g. Nguyen, David Viterbo, Ranjith P. Anand, Lauren Verra, Laura Sloan, Guy-franck Richard, Catherine H FreudenreichAbstract:Trinucleotide repeats are a source of genome instability, causing replication fork stalling, Chromosome Fragility, and impaired repair. Specialized helicases play an important role in unwinding DNA structures to maintain genome stability. The Srs2 helicase unwinds DNA hairpins, facilitates replication, and prevents repeat instability and Fragility. However, since Srs2 is a multifunctional protein with helicase activity and the ability to displace Rad51 recombinase, it was unclear which functions were required for its various protective roles. Here, using SRS2 separation-of-function alleles, we show that in the absence of Srs2 recruitment to PCNA or in helicase-deficient mutants, breakage at a CAG/CTG repeat increases. We conclude that Srs2 interaction with PCNA allows the helicase activity to unwind fork-blocking CAG/CTG hairpin structures to prevent breaks. Independently of PCNA binding, Srs2 also displaces Rad51 from nascent strands to prevent recombination-dependent repeat expansions and contractions. By 2D gel electrophoresis, we detect two different kinds of structured intermediates or joint molecules (JMs). Some JMs are Rad51-independent and exhibit properties of reversed forks, including being processed by the Exo1 nuclease. In addition, in a helicase-deficient mutant, Rad51-dependent JMs are detected, probably corresponding to recombination between sisters. These results clarify the many roles of Srs2 in facilitating replication through fork-blocking hairpin lesions.
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RTEL1 Inhibits Trinucleotide Repeat Expansions and Fragility
Cell reports, 2014Co-Authors: Aisling Frizzell, Catherine H Freudenreich, Jennifer H.g. Nguyen, Mark I.r. Petalcorin, Katherine D. Turner, Simon J. Boulton, Robert S. LahueAbstract:Human RTEL1 is an essential, multifunctional helicase that maintains telomeres, regulates homologous recombination, and helps prevent bone marrow failure. Here, we show that RTEL1 also blocks trinucleotide repeat expansions, the causal mutation for 17 neurological diseases. Increased expansion frequencies of (CTG⋅CAG) repeats occurred in human cells following knockdown of RTEL1, but not the alternative helicase Fbh1, and purified RTEL1 efficiently unwound triplet repeat hairpins in vitro. The expansion-blocking activity of RTEL1 also required Rad18 and HLTF, homologs of yeast Rad18 and Rad5. These findings are reminiscent of budding yeast Srs2, which inhibits expansions, unwinds hairpins, and prevents triplet-repeat-induced Chromosome Fragility. Accordingly, we found expansions and Fragility were suppressed in yeast srs2 mutants expressing RTEL1, but not Fbh1. We propose that RTEL1 serves as a human analog of Srs2 to inhibit (CTG⋅CAG) repeat expansions and Fragility, likely by unwinding problematic hairpins.
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Chromosome Fragility molecular mechanisms and cellular consequences
Frontiers in Bioscience, 2007Co-Authors: Catherine H FreudenreichAbstract:Fragile Sites are regions of genomes that are prone to breakage. In human cells, rare fragile sites are due to expansion of repetitive sequences which have been either shown or predicted to form DNA secondary structures such as hairpins, cruciforms, and quadruplexes. For human common fragile sites, which are components of normal chromatin structure, are induced by replication inhibitors, and encompass much larger regions (100s-1000s of kilobases) it has been more difficult to define particular sequence elements responsible for Fragility. However recent progress reviewed here in understanding the link between replication and Fragility, as well as identification of proteins and conditions needed to prevent Chromosome Fragility, have shed some light onto the reasons for breakage at common fragile sites. In addition, the discovery of several types of natural fragile sites on yeast Chromosomes and the characterization of associated deletions, duplications, and translocations, has revealed potential mechanisms for Fragility and for the chromosomal rearrangements that follow. An understanding of these events will provide insight into the generation of cancer, since deletions and rearrangements at human common fragile sites and associated tumor suppressor genes are an early event in tumorigenesis.
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an at rich sequence in human common fragile site fra16d causes fork stalling and Chromosome breakage in s cerevisiae
Molecular Cell, 2007Co-Authors: Haihua Zhang, Catherine H FreudenreichAbstract:Common fragile sites are regions of human Chromosomes prone to breakage. Fragile site FRA16D spans the WWOX/FOR tumor suppressor gene and has been linked to cancer-causing deletions and translocations. Using a genetic assay in yeast, we found that a short AT-rich region (Flex1) within FRA16D increases Chromosome Fragility, whereas three other sequences within FRA16D do not. To our knowledge, this is the first identification of a sequence element within a common fragile site that increases Chromosome Fragility. The Fragility of Flex1 was exacerbated by the absence of Rad52 or the presence of hydroxyurea. Flex1 contains a polymorphic AT repeat predicted to form a DNA structure, and two-dimensional gel analysis showed accumulation of stalled replication forks at the Flex1 sequence that was dependent on AT length. Our data suggest that the FRA16D Flex1 sequence causes increased Chromosome breakage by forming secondary structures that stall replication fork progression.
Massimo Bogliolo - One of the best experts on this subject based on the ideXlab platform.
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The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.
NPJ breast cancer, 2019Co-Authors: Gisella Figlioli, Massimo Bogliolo, Irene Catucci, Roser Pujol, Laura Caleca, Sandra Viz Lasheras, Johanna I. Kiiski, Taru A. Muranen, Daniel R. Barnes, Joe DennisAbstract:Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and Chromosome Fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and Chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.
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Individuals with FANCM biallelic mutations do not develop Fanconi anemia, but show risk for breast cancer, chemotherapy toxicity and may display Chromosome Fragility
Genetics in medicine : official journal of the American College of Medical Genetics, 2017Co-Authors: Irene Catucci, Massimo Bogliolo, Ana Osorio, Brita Arver, Guido Neidhardt, Federica Zanardi, Mirko Riboni, Simone Minardi, Roser Pujol, Jacopo AzzolliniAbstract:PurposeMonoallelic germ-line mutations in the BRCA1/FANCS, BRCA2/FANCD1 and PALB2/FANCN genes confer high risk of breast cancer. Biallelic mutations in these genes cause Fanconi anemia (FA), characterized by malformations, bone marrow failure, Chromosome Fragility, and cancer predisposition (BRCA2/FANCD1 and PALB2/FANCN), or an FA-like disease presenting a phenotype similar to FA but without bone marrow failure (BRCA1/FANCS). FANCM monoallelic mutations have been reported as moderate risk factors for breast cancer, but there are no reports of any clinical phenotype observed in carriers of biallelic mutations.MethodsBreast cancer probands were subjected to mutation analysis by sequencing gene panels or testing DNA damage response genes.ResultsFive cases homozygous for FANCM loss-of-function mutations were identified. They show a heterogeneous phenotype including cancer predisposition, toxicity to chemotherapy, early menopause, and possibly Chromosome Fragility. Phenotype severity might correlate with mutation position in the gene.ConclusionOur data indicate that biallelic FANCM mutations do not cause classical FA, providing proof that FANCM is not a canonical FA gene. Moreover, our observations support previous findings suggesting that FANCM is a breast cancer-predisposing gene. Mutation testing of FANCM might be considered for individuals with the above-described clinical features.
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fanconi anemia a model disease for studies on human genetics and advanced therapeutics
Current Opinion in Genetics & Development, 2015Co-Authors: Massimo Bogliolo, Jordi SurrallésAbstract:Fanconi anemia (FA) is characterized by bone marrow failure, malformations, and Chromosome Fragility. We review the recent discovery of FA genes and efforts to develop genetic therapies for FA in the last five years. Because current data exclude FANCM as an FA gene, 15 genes remain bona fide FA genes and three (FANCO, FANCR and FANCS) cause an FA like syndrome. Monoallelic mutations in 6 FA associated genes (FANCD1, FANCJ, FANCM, FANCN, FANCO and FANCS) predispose to breast and ovarian cancer. The products of all these genes are involved in the repair of stalled DNA replication forks by unhooking DNA interstrand cross-links and promoting homologous recombination. The genetic characterization of patients with FA is essential for developing therapies, including hematopoietic stem cell transplantation from a savior sibling donor after embryo selection, gene therapy, or genome editing using genetic recombination or engineered nucleases. Newly acquired knowledge about FA promises to provide therapeutic strategies in the near future.
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histone h2ax and fanconi anemia fancd2 function in the same pathway to maintain Chromosome stability
The EMBO Journal, 2007Co-Authors: Massimo Bogliolo, Elsa Callen, Maria Castella, A Creus, Ricard Marcos, Alex Lyakhovich, Enrico Cappelli, M J Ramirez, Reinhard Kalb, Kornelia NevelingAbstract:Fanconi anemia (FA) is a Chromosome Fragility syndrome characterized by bone marrow failure and cancer susceptibility. The central FA protein FANCD2 is known to relocate to chromatin upon DNA damage in a poorly understood process. Here, we have induced subnuclear accumulation of DNA damage to prove that histone H2AX is a novel component of the FA/BRCA pathway in response to stalled replication forks. Analyses of cells from H2AX knockout mice or expressing a nonphosphorylable H2AX (H2AXS136A/S139A) indicate that phosphorylated H2AX (γH2AX) is required for recruiting FANCD2 to chromatin at stalled replication forks. FANCD2 binding to γH2AX is BRCA1-dependent and cells deficient or depleted of H2AX show an FA-like phenotype, including an excess of chromatid-type chromosomal aberrations and hypersensitivity to MMC. This MMC hypersensitivity of H2AX-deficient cells is not further increased by depleting FANCD2, indicating that H2AX and FANCD2 function in the same pathway in response to DNA damage-induced replication blockage. Consequently, histone H2AX is functionally connected to the FA/BRCA pathway to resolve stalled replication forks and prevent Chromosome instability.
B Tedeschi - One of the best experts on this subject based on the ideXlab platform.
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increased Chromosome Fragility in lymphocytes of short normal children treated with recombinant human growth hormone
Human Genetics, 1993Co-Authors: B Tedeschi, Gian Luigi Spadoni, Maria Lucia Sanna, P Vernole, Daniela Caporossi, Stefano Cianfarani, B Nicoletti, B BoscheriniAbstract:A few years ago it was reported that some growth-hormone-deficient children had developed leukemia following therapy with human growth hormone. This raised concern that this therapy may stimulate tumor development. Since it is known that the tendency to develop cancer is closely related to Chromosome breakage, we decided to investigate whether recombinant human growth hormone (rhGH) therapy can increase Chromosome Fragility. Ten short normal children were studied during their first year of treatment. Lymphocytes were collected at 0, 6 and 12 months of rhGH therapy, and we assessed the rate of spontaneous Chromosome aberrations, the frequency of sister chromatid exchanges, the proliferative rate indices, the expression of common fragile sites induced by aphidicolin, and the sensitivity towards the radiomimetic action of bleomycin. At 6 months of therapy, there was a significant increase in bleomycin-induced Chromosome aberrations, which remained unchanged after 1 year of treatment. An increase in spontaneous Chromosome rearrangements at 6 and 12 months of therapy was also observed. These findings are further supported by data obtained from the analysis of 16 short normal children already on rhGH therapy.
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increased Chromosome Fragility in lymphocytes of short normal children treated with recombinant human growth hormone
Pediatric Research, 1993Co-Authors: Gian Luigi Spadoni, B Tedeschi, Maria Lucia Sanna, P Vernole, Daniela Caporossi, Stefano Cianfarani, B Nicoletti, B BoscheriniAbstract:The report, few years ago, of some growth hormone-deficient children having developed leukemia following therapy with human growth hormone, raised concern about a possible stimulatory effect of this therapy on tumor development. Since it is known that proneness to cancer is related to Chromosome breakage, we decided to investigate whether recombinant human growth hormone (rhGH) therapy might increase Chromosome Fragility. Ten short-normal children (age: 6-11 yrs. mean height: −2.5 SD; mean growth rate: 4.1 cm/yr; mean bone age: −2.5 SD) were studied. Lymphocytes were collected at 0, 6 and 12 months of therapy, and the rate of spontaneous Chromosome aberrations, the frequency of sister chromatid exchanges, the proiterative rate indices, the expression of common fragile sites induced by aphidicolin, and the sensitivity towards the radiomimetic action of bleomicin (BLM) were assessed. The mean frequency of BLM-induced Chromosome aberrations increased from the pretherapy 0.11 breaks/cell (b/c) value to 0.23 b/c at 6 months of therapy (p<0.01), and remained at the same level (0.22 b/c) at 12 months. The frequency of damaged cells, showed a significative difference (p<0.05) between the pretherapy value (0.09) and the value found in the cultures performed at 6 and 12 months of therapy (0.14). An increase in spontaneous Chromosome rearrangements at 6 and 12 months of therapy was also observed. These findings are supported by data obtained from the analysis of 16 short normal children already on rhGH therapy. Our data point out the need for rhGH to be given only in the strictest of indications. The opportunity of starting rhGH therapy should be carefully questioned when short stature is associated with conditions at risk for the development of tumours, for an increased chromosomal radiosensitivity, e.g. Down syndrome, or tor increased chromosomal breakage, e.g. Fanconi anemia and Bloom syndrome.
Gian Luigi Spadoni - One of the best experts on this subject based on the ideXlab platform.
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increased Chromosome Fragility in lymphocytes of short normal children treated with recombinant human growth hormone
Human Genetics, 1993Co-Authors: B Tedeschi, Gian Luigi Spadoni, Maria Lucia Sanna, P Vernole, Daniela Caporossi, Stefano Cianfarani, B Nicoletti, B BoscheriniAbstract:A few years ago it was reported that some growth-hormone-deficient children had developed leukemia following therapy with human growth hormone. This raised concern that this therapy may stimulate tumor development. Since it is known that the tendency to develop cancer is closely related to Chromosome breakage, we decided to investigate whether recombinant human growth hormone (rhGH) therapy can increase Chromosome Fragility. Ten short normal children were studied during their first year of treatment. Lymphocytes were collected at 0, 6 and 12 months of rhGH therapy, and we assessed the rate of spontaneous Chromosome aberrations, the frequency of sister chromatid exchanges, the proliferative rate indices, the expression of common fragile sites induced by aphidicolin, and the sensitivity towards the radiomimetic action of bleomycin. At 6 months of therapy, there was a significant increase in bleomycin-induced Chromosome aberrations, which remained unchanged after 1 year of treatment. An increase in spontaneous Chromosome rearrangements at 6 and 12 months of therapy was also observed. These findings are further supported by data obtained from the analysis of 16 short normal children already on rhGH therapy.
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increased Chromosome Fragility in lymphocytes of short normal children treated with recombinant human growth hormone
Pediatric Research, 1993Co-Authors: Gian Luigi Spadoni, B Tedeschi, Maria Lucia Sanna, P Vernole, Daniela Caporossi, Stefano Cianfarani, B Nicoletti, B BoscheriniAbstract:The report, few years ago, of some growth hormone-deficient children having developed leukemia following therapy with human growth hormone, raised concern about a possible stimulatory effect of this therapy on tumor development. Since it is known that proneness to cancer is related to Chromosome breakage, we decided to investigate whether recombinant human growth hormone (rhGH) therapy might increase Chromosome Fragility. Ten short-normal children (age: 6-11 yrs. mean height: −2.5 SD; mean growth rate: 4.1 cm/yr; mean bone age: −2.5 SD) were studied. Lymphocytes were collected at 0, 6 and 12 months of therapy, and the rate of spontaneous Chromosome aberrations, the frequency of sister chromatid exchanges, the proiterative rate indices, the expression of common fragile sites induced by aphidicolin, and the sensitivity towards the radiomimetic action of bleomicin (BLM) were assessed. The mean frequency of BLM-induced Chromosome aberrations increased from the pretherapy 0.11 breaks/cell (b/c) value to 0.23 b/c at 6 months of therapy (p<0.01), and remained at the same level (0.22 b/c) at 12 months. The frequency of damaged cells, showed a significative difference (p<0.05) between the pretherapy value (0.09) and the value found in the cultures performed at 6 and 12 months of therapy (0.14). An increase in spontaneous Chromosome rearrangements at 6 and 12 months of therapy was also observed. These findings are supported by data obtained from the analysis of 16 short normal children already on rhGH therapy. Our data point out the need for rhGH to be given only in the strictest of indications. The opportunity of starting rhGH therapy should be carefully questioned when short stature is associated with conditions at risk for the development of tumours, for an increased chromosomal radiosensitivity, e.g. Down syndrome, or tor increased chromosomal breakage, e.g. Fanconi anemia and Bloom syndrome.