Disease relevance of Fancc

• Here we show that the Fanconi anemia complementation group C protein (Fancc) is necessary for proper function of the DNA damage-induced G2/M checkpoint in vitro and in vivo [1].
• Fancc(-/-) HSCs transduced with a retrovirus encoding rFancc exhibited a repopulating ability that approached wild-type levels [2].
• Interestingly, approximately 30% of primary recipients (7 of 22) transplanted with uncorrected Fancc(-/-) cells developed a range of hematopoietic abnormalities including pancytopenia and BM hypoplasia similar to individuals with FA [2].
• Conversely, inhibition of PKR function by enforced expression of a dominant-negative inhibitory mutant of PKR (PKRDelta6) substantially reduced the IFN and dsRNA hypersensitivity of FANCC(-/-) cells [3].
• Developmental expression of the Fac gene correlates with congenital defects in Fanconi anemia patients [4].

High impact information on Fancc

• Inactivation of Fac in mice produces inducible chromosomal instability and reduced fertility reminiscent of Fanconi anaemia [5].
• Further, recipients reconstituted with the surviving Fancc(-/-) cells have a high incidence of cytogenetic abnormalities and myeloid malignancies that are associated with an acquired resistance to tumor necrosis factor alpha (TNF-alpha) [6].
• Ex vivo culture of Fancc-/- stem/progenitor cells predisposes cells to undergo apoptosis, and surviving stem/progenitor cells display cytogenetic abnormalities and an increased risk of malignancy [6].
• Collectively, these data indicate that the intrinsic defects in the genomic stability of Fancc(-/-) stem/progenitor cells provide a selective pressure for cells that are resistant to apoptosis and have a propensity for the evolution to clonal hematopoiesis and malignancy [6].
• Collectively, these data demonstrate that p53 and Fancc interact functionally to regulate apoptosis and tumorigenesis in Fancc-deficient cells [7].

Chemical compound and disease context of Fancc

• Mice homozygous for Fac mutations show reduced fertility and hypersensitivity to induction of chromosomal aberrations by MMC and DEB [8].

Biological context of Fancc

• These results suggested that the altered redox state likely present in Fancc(-/-) Sod1(-/-) hematopoietic progenitors was responsible for an impairment of cell proliferation or survival [9].
• Mice mutant for the Fanconi anemia complementation group C locus (Fancc) have reduced germ cell numbers as early as embryonic day E12.5, suggesting the Fancc protein functions prior to meiosis in both sexes [10].
• Here, we tested whether alterations in the activation of a redox-dependent pathway may participate in the pro-apoptotic phenotype of primary Fancc -/- cells in response to oxidative stress [11].
• The mouse cDNA (Facc) shares 79% amino acid sequence similarity with the human gene product [12].
• In this report, we localized Facc to mouse Chromosome (Chr) 13 and its rat homolog to rat Chr 17 [13].

Anatomical context of Fancc

• The second phenotypic feature of Fancc(-/-) Sod1(-/-) mice was that of bone marrow hypocellularity accompanied by significant decreases in peripheral blood erythrocyte and leukocyte numbers as compared with wild-type controls [9].
• This study demonstrates Fancc is required for mitotic proliferation of primordial germ cells [10].
• Supporting our hypothesis that nitric oxide (NO) production might be a common effector in this sensitivity, we found that cytokine-mediated growth inhibition of Fancc(-/-) bone marrow cells was prevented by inhibiting NO synthase activity [14].
• Retroviral-mediated expression of recombinant Fancc enhances the repopulating ability of Fancc-/- hematopoietic stem cells and decreases the risk of clonal evolution [2].
• Fancc(-/-) mice injected with granulocyte colony-stimulating factor, erythropoietin, or both cytokines showed a delay in mitomycin C (MMC)-induced bone marrow (BM) failure compared to untreated mice [15].

Associations of Fancc with chemical compounds

• Interestingly, Fancc(-/-) hematopoietic cells also exhibited increased growth inhibition on exposure to 2 distinct NO-generating agents, S-nitroso-N-acetyl-D, L-penicillamine (SNAP) and diethylenetriamine nitric oxide adduct (DETA/NO) [14].
• Suppression of apoptosis by the pan-caspase inhibitor benzyloxycarbonyl-VAD-fluoromethyl ketone dramatically increased senescent Fancc-/- progenitor cells [16].

Regulatory relationships of Fancc

• Overexpression of wild-type PKR-sensitized FANCC(-/-) cells to apoptosis induced by IFN-gamma and dsRNA [3].
• Short-term granulocyte colony-stimulating factor and erythropoietin treatment enhances hematopoiesis and survival in the mitomycin C-conditioned Fancc(-/-) mouse model, while long-term treatment is ineffective [15].

Other interactions of Fancc

• The characteristics of the Fancg(-/-) mice closely resemble those reported for Fancc and Fanca null mice, supporting a tight interdependence of the corresponding gene products in a common pathway [17].
• In contrast, genetic disruption of both Fancc and Atm did not cooperate in the G2 checkpoint [1].
• Impaired type I IFN-induced Jak/STAT signaling in FA-C cells and abnormal CD4+ Th cell subsets in Fancc-/- mice [18].
• We conclude that mutation in the Fac protein induces heightened sensitivity to TNF-alpha and Fas receptor ligation, results that may explain the mechanism of anemia in FA-C patients [19].
• Consequently, loss of a functional FANCC results in decreased activation of STAT1 following IFN-gamma stimulation [18].

Analytical, diagnostic and therapeutic context of Fancc

• Determination of the mitotic index of primordial germ cells by BrdU incorporation shows that germ cells in Fancc(-/-) mice proliferate significantly more slowly than littermate controls [10].
• This paper describes the distribution of Fac transcripts during murine development (8-19.5 days p.c.), using RNA in situ hybridization [4].

References