Gene Summary

Gene:FANCC; FA complementation group C
Aliases: FA3, FAC, FACC
Summary:The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group C. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:Fanconi anemia group C protein
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

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Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (1)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

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Fanconi Anemia - Complementation Group C

Latest Publications

Ramanagoudr-Bhojappa R, Carrington B, Ramaswami M, et al.
Multiplexed CRISPR/Cas9-mediated knockout of 19 Fanconi anemia pathway genes in zebrafish revealed their roles in growth, sexual development and fertility.
PLoS Genet. 2018; 14(12):e1007821 [PubMed] Free Access to Full Article Related Publications
Fanconi Anemia (FA) is a genomic instability syndrome resulting in aplastic anemia, developmental abnormalities, and predisposition to hematological and other solid organ malignancies. Mutations in genes that encode proteins of the FA pathway fail to orchestrate the repair of DNA damage caused by DNA interstrand crosslinks. Zebrafish harbor homologs for nearly all known FA genes. We used multiplexed CRISPR/Cas9-mediated mutagenesis to generate loss-of-function mutants for 17 FA genes: fanca, fancb, fancc, fancd1/brca2, fancd2, fance, fancf, fancg, fanci, fancj/brip1, fancl, fancm, fancn/palb2, fanco/rad51c, fancp/slx4, fancq/ercc4, fanct/ube2t, and two genes encoding FA-associated proteins: faap100 and faap24. We selected two indel mutations predicted to cause premature truncations for all but two of the genes, and a total of 36 mutant lines were generated for 19 genes. Generating two independent mutant lines for each gene was important to validate their phenotypic consequences. RT-PCR from homozygous mutant fish confirmed the presence of transcripts with indels in all genes. Interestingly, 4 of the indel mutations led to aberrant splicing, which may produce a different protein than predicted from the genomic sequence. Analysis of RNA is thus critical in proper evaluation of the consequences of the mutations introduced in zebrafish genome. We used fluorescent reporter assay, and western blots to confirm loss-of-function for several mutants. Additionally, we developed a DEB treatment assay by evaluating morphological changes in embryos and confirmed that homozygous mutants from all the FA genes that could be tested (11/17), displayed hypersensitivity and thus were indeed null alleles. Our multiplexing strategy helped us to evaluate 11 multiple gene knockout combinations without additional breeding. Homozygous zebrafish for all 19 single and 11 multi-gene knockouts were adult viable, indicating FA genes in zebrafish are generally not essential for early development. None of the mutant fish displayed gross developmental abnormalities except for fancp-/- fish, which were significantly smaller in length than their wildtype clutch mates. Complete female-to-male sex reversal was observed in knockouts for 12/17 FA genes, while partial sex reversal was seen for the other five gene knockouts. All adult females were fertile, and among the adult males, all were fertile except for the fancd1 mutants and one of the fancj mutants. We report here generation and characterization of zebrafish knockout mutants for 17 FA disease-causing genes, providing an integral resource for understanding the pathophysiology associated with the disrupted FA pathway.

Río P, Navarro S, Bueren JA
Advances in Gene Therapy for Fanconi Anemia.
Hum Gene Ther. 2018; 29(10):1114-1123 [PubMed] Related Publications
Fanconi anemia (FA) is a rare inherited disease that is associated with bone marrow failure and a predisposition to cancer. Previous clinical trials emphasized the difficulties that accompany the use of gene therapy to treat bone marrow failure in patients with FA. Nevertheless, the discovery of new drugs that can efficiently mobilize hematopoietic stem cells (HSCs) and the development of optimized procedures for transducing HSCs, using safe, integrative vectors, markedly improved the efficiency by which the phenotype of hematopoietic repopulating cells from patients with FA can be corrected. In addition, these achievements allowed the demonstration of the in vivo proliferation advantage of gene-corrected FA repopulating cells in immunodeficient mice. Significantly, new gene therapy trials are currently ongoing to investigate the progressive restoration of hematopoiesis in patients with FA by gene-corrected autologous HSCs. Further experimental studies are focused on the ex vivo transduction of unpurified FA HSCs, using new pseudotyped vectors that have HSC tropism. Because of the resistance of some of these vectors to serum complement, new strategies for in vivo gene therapy for FA HSCs are in development. Finally, because of the rapid advancements in gene-editing techniques, correction of CD34

Li N, Ding L, Li B, et al.
Functional analysis of Fanconi anemia mutations in China.
Exp Hematol. 2018; 66:32-41.e8 [PubMed] Related Publications
Fanconi anemia (FA) is a rare recessive disease characterized by progressive bone marrow failure, congenital abnormalities, and increased incidence of cancers. To date, mutations in 22 genes can cause FA or an FA-like phenotype. In China, in addition to clinical information, FA diagnosis primarily relies on genetic sequencing because the chromosome breakage test is rarely performed. Here, we employed multiple genetic diagnostic tools (DNA sequencing, multiplex ligation-dependent probe amplification, and chromosome microarray) and a variant-based functional assay platform to investigate the genetic cause in 25 Chinese suspected FA patients. A total of 45 distinct candidate variants were detected in six FA genes (FA-A, FA-B, FA-C, FA-D2, FA-G, and FA-J), of which 36 were novel. Eight missense variants and one indel variant were unable to restore FANCD2 mono-ubiquitination and mitomycin C resistance in a panel of FA indicator cell lines, indicating that these mutations are deleterious. Three missense variants (FANCA-L424V, FANCC-E273K, and FANCG-A153G) were harmless. Finally, 23 patients were molecularly diagnosed with FA, consistent with their clinical phenotype. In the FA-A subgroup, large deletions accounted for 14% of the disease-causing variants. We have established a comprehensive molecular diagnostic workflow for Chinese FA patients that can substitute for standard FA cytogenetic analysis.

Kulanuwat S, Jungtrakoon P, Tangjittipokin W, et al.
Fanconi anemia complementation group C protection against oxidative stress‑induced β‑cell apoptosis.
Mol Med Rep. 2018; 18(2):2485-2491 [PubMed] Related Publications
Diabetes mellitus (DM) and other glucose metabolism abnormalities are commonly observed in individuals with Fanconi anemia (FA). FA causes an impaired response to DNA damage due to genetic defects in a cluster of genes encoded proteins involved in DNA repair. However, the mechanism by which FA is associated with DM has not been clearly elucidated. Fanconi anemia complementation group C (FANCC) is a component of FA nuclear clusters. Evidence suggests that cytoplasmic FANCC has a role in protection against oxidative stress‑induced apoptosis. As oxidative stress‑mediated β‑cell dysfunction is one of the contributors to DM pathogenesis, the present study aimed to investigate the role of FANCC in pancreatic β‑cell response to oxidative stress. Small interfering RNA‑mediated FANCC suppression caused a loss of protection against oxidative stress‑induced apoptosis, and that overexpression of FANCC reduced this effect in the human 1.1B4 β‑cell line. These findings were confirmed by Annexin V‑FITC/PI staining, caspase 3/7 activity assay, and expression levels of anti‑apoptotic and pro‑apoptotic genes. Insulin and glucokinase mRNA expression were also decreased in FANCC‑depleted 1.1B4 cells. The present study demonstrated the role of FANCC in protection against oxidative stress‑induced β‑cell apoptosis and established another mechanism that associates FANCC deficiency with β‑cell dysfunction. The finding that FANCC overexpression reduced β‑cell apoptosis advances the potential for an alternative approach to the treatment of DM caused by FANCC defects.

Velimezi G, Robinson-Garcia L, Muñoz-Martínez F, et al.
Map of synthetic rescue interactions for the Fanconi anemia DNA repair pathway identifies USP48.
Nat Commun. 2018; 9(1):2280 [PubMed] Free Access to Full Article Related Publications
Defects in DNA repair can cause various genetic diseases with severe pathological phenotypes. Fanconi anemia (FA) is a rare disease characterized by bone marrow failure, developmental abnormalities, and increased cancer risk that is caused by defective repair of DNA interstrand crosslinks (ICLs). Here, we identify the deubiquitylating enzyme USP48 as synthetic viable for FA-gene deficiencies by performing genome-wide loss-of-function screens across a panel of human haploid isogenic FA-defective cells (FANCA, FANCC, FANCG, FANCI, FANCD2). Thus, as compared to FA-defective cells alone, FA-deficient cells additionally lacking USP48 are less sensitive to genotoxic stress induced by ICL agents and display enhanced, BRCA1-dependent, clearance of DNA damage. Consequently, USP48 inactivation reduces chromosomal instability of FA-defective cells. Our results highlight a role for USP48 in controlling DNA repair and suggest it as a potential target that could be therapeutically exploited for FA.

Dimishkovska M, Kotori VM, Gucev Z, et al.
Novel Founder Mutation in
Balkan Med J. 2018; 35(1):108-111 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Fanconi anemia is a rare autosomal recessive or X-linked disorder characterised by clinical and genetic heterogeneity. Most fanconi anemia patients harbour homozygous or double heterozygous mutations in the
CASE REPORT: The novel
CONCLUSION: The finding of the

Kessous R, Octeau D, Klein K, et al.
Distinct homologous recombination gene expression profiles after neoadjuvant chemotherapy associated with clinical outcome in patients with ovarian cancer.
Gynecol Oncol. 2018; 148(3):553-558 [PubMed] Related Publications
OBJECTIVE: The expression of homologous recombination (HR) genes in high grade ovarian cancer (HGOC) samples from debulking surgeries were correlated to outcomes in patients selected for chemotherapy treatment regimens.
STUDY DESIGN: RNA was extracted from 96 fresh frozen tumor samples from debulking surgeries from chemotherapy naïve patients with HGOC (primary derived surgeries (PDS), n = 55) or following neoadjuvant chemotherapy treatment (NACT), n = 41). The samples were selected for high tumor content by a gynecological pathologist, and cancer cell content was further confirmed using a percent tumor content covariate, and mutation score covariate analysis. Gene expression analysis was performed using a tailored NanoString-based Pancancer Pathway Panel. Cox proportional hazard regression models were used to assess the associations between the expression of 19 HR genes and survival.
RESULTS: In the PDS group, over-expression of six HR genes (C11orf30, NBN, FANCF, FANCC, FANCB, RAD50) was associated with improved outcome, in contrast to the NACT group where four HR genes (BRCA2, TP53, FANCB, RAD51) were associated with worse outcome. With the adding extent of debulking as a covariate, three HR genes (NBN, FANCF, RAD50), and only one HR gene (RAD51) remained significantly associated with survival in PDS and NACT groups, respectively.
CONCLUSION: Distinct HR expression profiles define subgroups associated with overall outcome in patients that are exposed to neoadjuvant chemotherapy and not only chemotherapy-naïve patients.

Shah CA, Broglie L, Hu L, et al.
Stat3 and CCAAT enhancer-binding protein β (C/ebpβ) activate Fanconi C gene transcription during emergency granulopoiesis.
J Biol Chem. 2018; 293(11):3937-3948 [PubMed] Free Access to Full Article Related Publications
Interferon consensus sequence-binding protein (Icsbp) is required for terminating emergency granulopoiesis, an episodic event responsible for granulocyte production in response to infections and a key component of the innate immune response. Icsbp inhibits the expression of Stat3 and C/ebpβ, transcription factors essential for initiating and sustaining granulopoiesis, and activates transcription of Fanconi C (

Moder M, Velimezi G, Owusu M, et al.
Parallel genome-wide screens identify synthetic viable interactions between the BLM helicase complex and Fanconi anemia.
Nat Commun. 2017; 8(1):1238 [PubMed] Free Access to Full Article Related Publications
Maintenance of genome integrity via repair of DNA damage is a key biological process required to suppress diseases, including Fanconi anemia (FA). We generated loss-of-function human haploid cells for FA complementation group C (FANCC), a gene encoding a component of the FA core complex, and used genome-wide CRISPR libraries as well as insertional mutagenesis to identify synthetic viable (genetic suppressor) interactions for FA. Here we show that loss of the BLM helicase complex suppresses FANCC phenotypes and we confirm this interaction in cells deficient for FA complementation group I and D2 (FANCI and FANCD2) that function as part of the FA I-D2 complex, indicating that this interaction is not limited to the FA core complex, hence demonstrating that systematic genome-wide screening approaches can be used to reveal genetic viable interactions for DNA repair defects.

Río P, Navarro S, Guenechea G, et al.
Engraftment and in vivo proliferation advantage of gene-corrected mobilized CD34
Blood. 2017; 130(13):1535-1542 [PubMed] Related Publications
Previous Fanconi anemia (FA) gene therapy studies have failed to demonstrate engraftment of gene-corrected hematopoietic stem and progenitor cells (HSPCs) from FA patients, either after autologous transplantation or infusion into immunodeficient mice. In this study, we demonstrate that a validated short transduction protocol of G-CSF plus plerixafor-mobilized CD34

Aftab I, Iram S, Khaliq S, et al.
Analysis of FANCC gene mutations (IVS4+4A>T, del322G, and R548X)in patients with Fanconi anemia in Pakistan.
Turk J Med Sci. 2017; 47(2):391-398 [PubMed] Related Publications
BACKGROUND/AIM: Fanconi anemia (FA) is an autosomal recessive disease determined by mutations in at least 16 genes, with distinct distributions in different populations. To the best of our knowledge, there are no reports regarding the molecular basis of the disease in FA patients in Pakistan. The current study aimed to determine the frequency of FANCC gene mutations, i.e. IVS4+4A>T, del322G, and R548X, in FA patients.
MATERIALS AND METHODS: Genomic DNA was obtained from 36 FA patients. All samples were analyzed by polymerase chain reaction and restriction fragment length polymorphism techniques.
RESULTS: Mutation IVS4+4A>T was identified in 26 (72.2%) patients. It was homozygous in 6 and heterozygous in 20 patients. Del322G and R548X were found with the following prevalences: del322G, 5.6%, and R548X, 5.6%. Patients with these two mutations were compound heterozygotes having concomitant IVS4+4A>T mutation.
CONCLUSION: These results suggest that mutation IVS4+4A>T is the most prevalent mutation in our group of patients. This analysis of Pakistani patients also suggests that there is no significant difference between IVS4+4A>T homozygotes and the rest of the patients with regard to severity of clinical phenotype.

D'Souza AM, Mark J, Demarcantonio M, et al.
Pediatric laryngeal carcinoma in a heterozygous carrier of Fanconi anemia.
Pediatr Blood Cancer. 2017; 64(8) [PubMed] Related Publications
A case of invasive, keratinizing squamous cell carcinoma of the larynx in an 8-year-old female treated with laryngectomy is presented. Perinatal exposure to human papilloma virus and constitutional heterozygosity for a FANCC mutation were identified, though FANCC heterozygosity is not known to be cancer predisposing. An additional tumor-associated mutation in NOTCH1 was also identified potentially contributing to oncogenesis. This case illustrates an exceedingly rare type of cancer in the pediatric population and discusses diagnostic workup, evaluation of risk factors for head and neck cancer, and treatment options.

van Twest S, Murphy VJ, Hodson C, et al.
Mechanism of Ubiquitination and Deubiquitination in the Fanconi Anemia Pathway.
Mol Cell. 2017; 65(2):247-259 [PubMed] Related Publications
Monoubiquitination and deubiquitination of FANCD2:FANCI heterodimer is central to DNA repair in a pathway that is defective in the cancer predisposition syndrome Fanconi anemia (FA). The "FA core complex" contains the RING-E3 ligase FANCL and seven other essential proteins that are mutated in various FA subtypes. Here, we purified recombinant FA core complex to reveal the function of these other proteins. The complex contains two spatially separate FANCL molecules that are dimerized by FANCB and FAAP100. FANCC and FANCE act as substrate receptors and restrict monoubiquitination to the FANCD2:FANCI heterodimer in only a DNA-bound form. FANCA and FANCG are dispensable for maximal in vitro ubiquitination. Finally, we show that the reversal of this reaction by the USP1:UAF1 deubiquitinase only occurs when DNA is disengaged. Our work reveals the mechanistic basis for temporal and spatial control of FANCD2:FANCI monoubiquitination that is critical for chemotherapy responses and prevention of Fanconi anemia.

Petersen GM
Familial pancreatic cancer.
Semin Oncol. 2016; 43(5):548-553 [PubMed] Free Access to Full Article Related Publications
Familial pancreatic cancer (FPC) includes those kindreds that contain at least two first-degree relatives with pancreatic ductal adenocarcinoma. At least 12 known hereditary syndromes or genes are associated with increased risk of developing pancreatic cancer, the foremost being BRCA2 and CDKN2A. Research into the identification of mutations in known cancer predisposition genes and through next-generation sequencing has revealed extensive heterogeneity. The development of genetic panel testing has enabled genetic risk assessment and predisposition testing to be routinely offered. Precision oncology has opened the possibility of "incidental" germline mutations that may have implications for family members. However, in both cases, evidence-based recommendations for managing patients and at-risk family members in light of genetic status remain emergent, with current practice based on expert opinion.

Chakkaramakkil Verghese S, Goloviznina NA, Kurre P
Phenotypic correction of Fanconi anemia cells in the murine bone marrow after carrier cell mediated delivery of lentiviral vector.
Stem Cell Res Ther. 2016; 7(1):170 [PubMed] Free Access to Full Article Related Publications
Fanconi anemia (FA) is an autosomal-recessive disorder associated with hematopoietic failure and it is a candidate for hematopoietic stem cell (HSC)-directed gene therapy. However, the characteristically reduced HSC numbers found in FA patients, their ineffective mobilization from the marrow, and re-oxygenation damage during ex vivo manipulation have precluded clinical success using conventional in vitro approaches. We previously demonstrated that lentiviral vector (LV) particles reversibly attach to the cell surface where they gain protection from serum complement neutralization. We reasoned that cellular delivery of LV to the bone marrow niche could avoid detrimental losses during FA HSC mobilization and in vitro modification. Here, we demonstrate that a VSV-G pseudotyped lentivector, carrying the FANCC transgene, can be transmitted from carrier to bystander cells. In cell culture and transplantation models of FA, we further demonstrate that LV carrier cells migrate along SDF-1α gradients and transfer vector particles that stably integrate and phenotypically correct the characteristic DNA alkylator sensitivity in murine and human FA-deficient target bystander cells. Altogether, we demonstrate that cellular homing mechanisms can be harnessed for the functional phenotype correction in murine FA hematopoietic cells.

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Cite this page: Cotterill SJ. FANCC, Cancer Genetics Web: Accessed:

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