First molecular-cytogenetic characterization of Fanconi anemia fragile sites in primary lymphocytes of FA-D2 patients in different stages of the disease

Filipović, Jelena; Joksić, Gordana; Vujić, Dragana; Joksić, Ivana; Mrasek, Kristin; Weise, Anja; Liehr, Thomas

doi:10.1186/s13039-016-0280-6

Cited by 10 publications

(7 citation statements)

References 38 publications

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“…Knies and colleagues (KNIES et al, 2012) also pointed out that single heterozygous mutation in one FA gene may be accompanied by the heterozygous mutation in other FA genes and lead to the disease. Our previous detailed molecular-cytogenetic investigation of these patients showed that cases 1 and 2 in which 7 and 8 variants were found, respectively, developed, at the time of sampling, severe BMF, had shorter telomeres, more telomere fusions and radial figures and different chromosomal breakage pattern compared to other FA-D2 patients (JOKSIC et al, 2012;FILIPOVIC et al, 2016). This is consistent with Chang's statement that great number of variants reflects the susceptibility of FA pathway.…”

Section: Discussionsupporting

confidence: 88%

Genotyping Fanconi anemia patients from Serbia reveals three novel FANCD2 variants

Filipovic-Trickovic¹,

Mandusic²,

Joksić³

et al. 2017

Genetika

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Fanconi anemia is rare inherited disease characterized by wide spectrum of congenital anomalies, progressive pancytopenia, and predisposition to hematological malignancies and solid tumors. Molecular genetic analysis of mutations in FANC genes is of a great importance for diagnosis confirmation, prenatal and carrier testing, as well as for prediction of chemotherapy outcome and disease complications. In this study we performed screening of frequently affected regions of FANCD2 gene for sequence variants in six unrelated FA-D2 patients in Serbia. This is the first molecular analysis of FANCD2 gene in Serbian FA-D2 patients. A total of 10 sequence variants were detected, one in homozygous, and nine in heterozygous state. Two variants were found within exons, and eight within introns, in deep intronic regions. In-silico analysis showed that among all detected variants one exon variant and three intron variants might have impact on splicing mechanism. Heterozygous variants found in intron 3, c.206-246delG; exon 26, c.2396 C>A and intron 28, c.2715+573 C>T were not previously reported. In-silico analysis revealed that among them, two (intron 3, c.206-246 delG and exon 26, c.2396 C>A) could be novel disease-causing mutations. Many variants were found in more than one patient, including those unreported, indicating their possible ethnic association. Great number of variants in some patients suggests their non-random emergence in Fanconi anemia pathway.

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Section: Discussionsupporting

confidence: 88%

Genotyping Fanconi anemia patients from Serbia reveals three novel FANCD2 variants

Filipovic-Trickovic¹,

Mandusic²,

Joksić³

et al. 2017

Genetika

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“…The FANC pathway is dysfunctional in individuals with Fanconi anemia (FA), a rare chromosome instability disorder characterized by bone marrow failure, predisposition to acute myeloid leukemia and epithelial cancers, and hypersensitivity to DNA interstrand crosslinks (ICLs) and endogenous aldehydes 16 – 18 . Chromosomal aberrations in FA patients occur preferentially at CFSs 19 – 21 . FANCD2, a key component of the FANC pathway, has been shown to relocalize to large genes encompassing CFSs after replication stress 22 , 23 and form foci at CFSs during mitosis, where it cooperates with the Bloom’s syndrome helicase (BLM) to prevent chromosomal abnormalities 24 , 25 .…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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Common 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.

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“…Slides were dehydrated with increasing concentrations of ethanol (70, 95, and 100 %), stained with 4′,6′-diamidino-2-phenylindole (DAPI)-containing Vectashield solution (Vector Laboratories Ltd, Peterborough, UK), and analysed under a Zeiss-Axioimager A1 microscope (Carl Zeiss, Jena, Germany), with the ISIS imaging software package (MetaSystems Hard & Software GmbH, Altlussheim, Germany). At least 200 complete metaphase spreads per sample were analysed, whereas the scoring criteria included determination of karyotype and indicators of chromosome damage (chromosome breaks, dicentric and ring chromosomes, acentric fragments, and radial figures) (18,19).…”

Section: Discussionmentioning

confidence: 99%

Yellow gentian root extract provokes concentration- and time-dependent response in peripheral blood mononuclear cells

Šobot

Drakulić

Joksić

et al. 2020

Archives of Industrial Hygiene and Toxicology

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Yellow gentian (Gentiana lutea L.), a medicinal plant widely used in traditional medicine, displays multiple biological effects, ranging from beneficial to toxic. Since many promising applications have been reported so far, our aim was to evaluate its potential concentration- and time- dependent cytotoxic and genotoxic effects in vitro. To that end we exposed human peripheral blood mononuclear cells to 0.5, 1, and 2 mg/mL of yellow gentian root extract (YGRE) to determine its effects on oxidative stress parameters [pro/antioxidant balance (PAB) and lipid peroxidation], DNA damage (alkaline comet assay and chromosome aberrations), and cell viability (trypan blue exclusion test). Cell viability decreased with increasing concentrations and treatment duration. Only the lowest YGRE concentration (0.5 mg/mL) increased oxidative stress but produced minor DNA damage and cytotoxicity. At higher concentrations, redox parameters returned to near control values. The percentage of chromosome aberrations and percentage of DNA in the comet tail increased with increased YGRE concentration after 48 h and declined after 72 h of treatment. This points to the activation of DNA repair mechanism (homologous recombination), evidenced by the formation of chromosomal radial figures after 72 h of treatment with the highest YGRE concentration of 2 mg/mL. Our results suggest that YGRE, despite induction of cytotoxic and genotoxic effects, activates cell repair mechanisms that counter oxidative and DNA lesions and induce cell death in highly damaged cells. Therefore, observed protective effects of yellow gentian after longer exposure could be a result of activated repair and removal of cells with irreparable damage.

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First molecular-cytogenetic characterization of Fanconi anemia fragile sites in primary lymphocytes of FA-D2 patients in different stages of the disease

Cited by 10 publications

References 38 publications

Genotyping Fanconi anemia patients from Serbia reveals three novel FANCD2 variants

Genotyping Fanconi anemia patients from Serbia reveals three novel FANCD2 variants

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

Yellow gentian root extract provokes concentration- and time-dependent response in peripheral blood mononuclear cells

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