Ultrastructure of Fanconi anemia fibroblasts

Willingale−Theune, Julia; Schweiger, Manfred; Hirsch‐Kauffmann, Monica; Meek, A E; Paulin−Levasseur, Micheline; Traub, Peter

doi:10.1242/jcs.93.4.651

Cited by 30 publications

(2 citation statements)

References 42 publications

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“…Compromises Mitotic Fidelity Through Exacerbation of Underlying SAC Defect FA-deficient cells consistently demonstrate features suggestive of abnormal cell division, and we and others have previously shown that the loss of FA-pathway proteins produces a phenotype consistent with SAC impairment (4,(44)(45)(46)(47)(48)(49). Above, we have confirmed the presence of an underlying SAC defect in Fancc-/cells and demonstrated that this defect is exacerbated in Fancc-/-; Mad2+/-cells.…”

Section: Combined Loss Of Fancc and Mad2supporting

confidence: 80%

Mitotic Errors Promote Genomic Instability and Leukemia in a Novel Mouse Model of Fanconi Anemia

et al. 2021

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Fanconi anemia (FA) is a disease of genomic instability and cancer. In addition to DNA damage repair, FA pathway proteins are now known to be critical for maintaining faithful chromosome segregation during mitosis. While impaired DNA damage repair has been studied extensively in FA-associated carcinogenesis in vivo, the oncogenic contribution of mitotic abnormalities secondary to FA pathway deficiency remains incompletely understood. To examine the role of mitotic dysregulation in FA pathway deficient malignancies, we genetically exacerbated the baseline mitotic defect in Fancc-/- mice by introducing heterozygosity of the key spindle assembly checkpoint regulator Mad2. Fancc-/-;Mad2+/- mice were viable, but died from acute myeloid leukemia (AML), thus recapitulating the high risk of myeloid malignancies in FA patients better than Fancc-/-mice. We utilized hematopoietic stem cell transplantation to propagate Fancc-/-; Mad2+/- AML in irradiated healthy mice to model FANCC-deficient AMLs arising in the non-FA population. Compared to cells from Fancc-/- mice, those from Fancc-/-;Mad2+/- mice demonstrated an increase in mitotic errors but equivalent DNA cross-linker hypersensitivity, indicating that the cancer phenotype of Fancc-/-;Mad2+/- mice results from error-prone cell division and not exacerbation of the DNA damage repair defect. We found that FANCC enhances targeting of endogenous MAD2 to prometaphase kinetochores, suggesting a mechanism for how FANCC-dependent regulation of the spindle assembly checkpoint prevents chromosome mis-segregation. Whole-exome sequencing revealed similarities between human FA-associated myelodysplastic syndrome (MDS)/AML and the AML that developed in Fancc-/-; Mad2+/- mice. Together, these data illuminate the role of mitotic dysregulation in FA-pathway deficient malignancies in vivo, show how FANCC adjusts the spindle assembly checkpoint rheostat by regulating MAD2 kinetochore targeting in cell cycle-dependent manner, and establish two new mouse models for preclinical studies of AML.

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Section: Combined Loss Of Fancc and Mad2supporting

confidence: 80%

Mitotic Errors Promote Genomic Instability and Leukemia in a Novel Mouse Model of Fanconi Anemia

et al. 2021

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Section: Combined Loss Of Fancc and Mad2supporting

confidence: 80%

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Cytoskeletal architecture of rat calvarial osteoclasts: Microfilaments, intermediate filaments, and nuclear matrix as demonstrated by detergent perfusion

1995

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Background: There have been few detailed transmission electron microscopic studies of the cytoskeleton of osteoclasts to date because of the high electron density of their cytoplasmic matrix, and there is a controversy concerning the presence of stress fibers in these cells.Methods: The cytoskeleton and nuclear matrix of osteoclasts in the rat cranium were studied by transmission electron microscopy after perfusing the organs with a mixture of Triton X-100 and a low concentration of glutaraldehyde to reduce the electron density of the intracellular matrix and by immunoelectron microscopy using anti-actin and anti-vimentin antibodies.Results: In osteoclasts, abundant microfilaments, 5-6 nm in diameter, extended across the cell organelles. These filaments were also observed just under the cell membrane facing the bone, but thick bundles of microfilaments were not noted. In the cytoplasm, there were fibers 1&12 nm in diameter, which were considered to be intermediate filaments distributed in the same pattern as microfilaments. Filamentous structures consisting both of the microfilaments and intermediate filaments connected the nuclei. Intermediate filaments linked nuclei at nuclear pores (near the euchromatin), and microfilaments connected nuclei at areas of the nuclear membrane containing nucleolus-associated heterochromatin. In the nuclear matrix after detergent treatment, thin filaments and intermediate-type filaments were found connecting the heterochromatins.Conclusions: Euchromatin is considered to be an active site of DNA and RNA synthesis. Our structural evidence has lead to the proposal that intermediate filaments in the cytoplasm may act as tracks for transmission of information between nuclei and guides for the transit of molecules through the pores.

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Ultrastructure of Fanconi anemia fibroblasts

Cited by 30 publications

References 42 publications

Mitotic Errors Promote Genomic Instability and Leukemia in a Novel Mouse Model of Fanconi Anemia

Mitotic Errors Promote Genomic Instability and Leukemia in a Novel Mouse Model of Fanconi Anemia

DataSheet_1.pdf

Cytoskeletal architecture of rat calvarial osteoclasts: Microfilaments, intermediate filaments, and nuclear matrix as demonstrated by detergent perfusion

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