Affinage

FANCF

Fanconi anemia group F protein · UniProt Q9NPI8

Length
374 aa
Mass
42.3 kDa
Annotated
2026-06-09
30 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FANCF is a nuclear adaptor protein essential for assembly of the Fanconi anemia (FA) core complex, which drives monoubiquitination of FANCD2 to enable repair of DNA interstrand cross-links (PMID:11063725, PMID:21915857). It functions as a flexible bridging subunit: its C-terminus binds FANCG to nucleate assembly of other FA proteins, while its N-terminus stabilizes FANCA/FANCG contacts and is required to recruit the FANCC/FANCE subcomplex (PMID:15262960). The C-terminal domain adopts a Cand1-like helical repeat fold whose two surface loops are critical both for interaction with other core complex components and for FANCD2 monoubiquitination and cellular resistance to mitomycin C (PMID:17082180). Loss of FANCF abolishes FANCD2 monoubiquitination and produces G2 arrest, chromosomal aberrations, sensitivity to cross-linking agents, and, in mice, defective gametogenesis and ovarian tumors, establishing its non-redundant role in the FA/BRCA pathway in vivo (PMID:21915857). The FANCC-FANCE-FANCF subcomplex is evolutionarily conserved to plants, where it additionally acts as an anti-crossover factor during meiotic recombination (PMID:36652992). FANCF expression is transcriptionally activated by ICSBP/IRF8 during myeloid differentiation (PMID:19801548) and is suppressed by p53-driven miR-30c, such that p53 loss in cancer cells upregulates FANCF and confers chemoresistance (PMID:31511498); silencing FANCF inactivates the FA/BRCA pathway and sensitizes breast and ovarian cancer cells to chemotherapeutic agents through p38/JNK MAPK signaling (PMID:22952942, PMID:23440494).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2000 High

    Established that FANCF is a physical member of a nuclear FA protein complex, placing it within the Fanconi anemia pathway rather than acting alone.

    Evidence Subcellular fractionation and reciprocal Co-IP across FA complementation groups in human lymphoblasts

    PMID:11063725

    Open questions at the time
    • Did not define which domains mediate each interaction
    • Did not establish the order of complex assembly
    • No direct link yet to a catalytic output of the complex
  2. 2004 High

    Resolved FANCF's role as a flexible adaptor that bridges distinct subcomplexes, explaining how it organizes core complex assembly.

    Evidence Systematic deletion/point-mutant Co-IP guided by human-Xenopus homology

    PMID:15262960

    Open questions at the time
    • No structural model of the interacting surfaces
    • Did not connect adaptor function to FANCD2 modification directly
  3. 2006 High

    Provided a structural basis for FANCF function by revealing a Cand1-like helical repeat domain and mapping surface loops required for both complex integrity and FANCD2 monoubiquitination.

    Evidence X-ray crystallography of the C-terminal domain plus mutagenesis with FANCD2 ubiquitination and MMC sensitivity readouts

    PMID:17082180

    Open questions at the time
    • Structure limited to the C-terminal domain; full-length and N-terminal architecture unresolved
    • Mechanistic analogy to Cand1's ubiquitin-ligase regulation not functionally tested
  4. 2009 Medium

    Identified an upstream transcriptional input, linking FANCF expression to myeloid differentiation via ICSBP/IRF8.

    Evidence ChIP identification of a FANCF promoter cis-element and cross-link repair epistasis in ICSBP-deficient cells

    PMID:19801548

    Open questions at the time
    • Single lab; cis-element not validated by reporter mutagenesis in the timeline
    • Relevance beyond myeloid lineage unknown
  5. 2011 High

    Confirmed in vivo that FANCF is required for FANCD2 activation and genome stability, and revealed organismal phenotypes of its loss.

    Evidence Fancf knockout mouse and MEFs assayed for FANCD2 monoubiquitination, chromosomal aberrations, drug sensitivity, and tumor incidence

    PMID:21915857

    Open questions at the time
    • Mechanism linking FA pathway loss to ovarian tumorigenesis not dissected
    • Tissue-specific gametogenesis defects not mechanistically explained
  6. 2012 Medium

    Demonstrated that FANCF depletion is a chemosensitization strategy in breast cancer, coupling FA pathway inactivation to MAPK-driven death.

    Evidence shRNA knockdown in MCF-7/T-47D with FANCD2 ubiquitination Western blot, apoptosis assays, and p38/JNK inhibitor experiments

    PMID:22952942

    Open questions at the time
    • Single lab, two cell lines; no in vivo confirmation
    • Mechanistic link between FA pathway loss and p38/JNK activation unresolved
  7. 2013 Medium

    Extended the chemosensitization model to ovarian cancer through JNK-dependent mitochondrial apoptosis.

    Evidence siRNA knockdown in OVCAR3 with FANCD2 ubiquitination/focus readouts, apoptosis flow cytometry, and JNK inhibitor experiments

    PMID:23440494

    Open questions at the time
    • Paper had figure assembly errors per corrigendum
    • Single cell line; mechanism of JNK activation not defined
  8. 2019 Medium

    Placed FANCF downstream of a p53–miR-30c axis, explaining how p53 status modulates FANCF levels and chemoresistance.

    Evidence Luciferase reporter for p53 binding to the miR-30c promoter, miR-30c manipulation with FANCF Western blot, and adriamycin sensitivity in p53-WT vs mutant cells

    PMID:31511498

    Open questions at the time
    • Single lab; direct miR-30c binding to FANCF transcript not fully mapped
    • Contribution of co-target REV1 versus FANCF to resistance not separated
  9. 2023 Medium

    Revealed a conserved FANCC-FANCE-FANCF subcomplex with a meiotic anti-crossover function, broadening FANCF's role beyond cross-link repair.

    Evidence Genetic screen, epistasis with CO-defective and MUS81 mutants, and physical interaction assays in Arabidopsis

    PMID:36652992

    Open questions at the time
    • Mechanistic detail limited; how the subcomplex limits crossovers not defined
    • Conservation of the meiotic anti-crossover role in mammals not demonstrated in the timeline

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the Cand1-like FANCF domain mechanistically couples core complex assembly to the FANCD2 ubiquitin ligase activity, and how this links to its meiotic anti-crossover function, remains unresolved.
  • No full-length structure of FANCF within the assembled core complex
  • Molecular basis of the anti-crossover activity unknown
  • Mechanism connecting FA pathway loss to p38/JNK signaling undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-1474165 Reproduction 2 R-HSA-73894 DNA Repair 2
Partners
FANCAFANCCFANCEFANCG
Complex memberships
FANCC-FANCE-FANCF subcomplexFanconi anemia core complex

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 FANCF forms a nuclear complex with FANCA, FANCC, and FANCG in human lymphoblasts. Each FA protein (except FANCD) is required for complex formation, as interactions were detected in wild-type and FA-D cells but not in lymphoblasts of other FA complementation groups. Subcellular fractionation and co-immunoprecipitation in human lymphoblasts across FA complementation groups Human molecular genetics High 11063725
2004 FANCF acts as a flexible adaptor protein in the FA core complex: its C-terminus interacts directly with FANCG to allow assembly of other FA proteins, while the N-terminus stabilizes interactions with FANCA and FANCG and is essential for binding of the FANCC/FANCE subcomplex. FANCF does not have a ROM-like function as previously suggested. Extensive mutagenesis study guided by human-Xenopus FANCF homology, co-immunoprecipitation of deletion/point mutants The Journal of biological chemistry High 15262960
2006 X-ray crystallography of the FANCF C-terminal domain reveals a helical repeat structure similar to Cand1, a regulator of a Cul1-Rbx1-Skp1-Fbox ubiquitin ligase complex. Two C-terminal loops are essential for FANCD2 monoubiquitination and cellular resistance to mitomycin C; mutations in this surface abolish interaction with other FA core complex components. X-ray crystallography of FANCF C-terminal domain; amino acid substitution mutagenesis with FANCD2 monoubiquitination assay and MMC sensitivity assay The Journal of biological chemistry High 17082180
2009 ICSBP/IRF8 directly activates transcription of FANCF during myeloid differentiation by binding a cis element in the FANCF promoter. ICSBP-deficient myeloid cells show impaired DNA cross-link repair in a FANCF-dependent manner. Chromatin co-immunoprecipitation to identify FANCF as an ICSBP target gene; FANCF promoter cis-element identification; DNA cross-link repair assay in ICSBP-deficient cells The Journal of biological chemistry Medium 19801548
2012 FANCF silencing by shRNA blocks FANCD2 monoubiquitination (inactivating the FA/BRCA pathway), inhibits cell proliferation, induces apoptosis and chromosome fragmentation, and sensitizes breast cancer cells to mitoxantrone. Sensitization involves activation of p38 and JNK MAPK pathways; BCRP expression is restored by p38 inhibitor SB203580. shRNA knockdown of FANCF in MCF-7 and T-47D cells; Western blot for FANCD2 monoubiquitination; MTT proliferation assay; apoptosis assay; p38/JNK pathway inhibitor experiments PloS one Medium 22952942
2013 FANCF silencing by siRNA inactivates the FA/BRCA pathway (decreasing FANCD2 monoubiquitination and focus formation), reduces cell proliferation, induces apoptosis, and sensitizes OVCAR3 ovarian cancer cells to adriamycin through JNK-dependent mitochondrial apoptosis pathway activation. siRNA knockdown in OVCAR3 cells; FANCD2 monoubiquitination and focus formation by Western blot and immunofluorescence; flow cytometry for apoptosis; JNK pathway inhibitor experiments Oncology reports Medium 23440494
2023 The FANCC-FANCE-FANCF subcomplex is evolutionarily conserved from vertebrates to plants (Arabidopsis). Physical interaction among FANCC, FANCE, and FANCF is conserved, and this subcomplex acts as an anti-crossover factor during meiotic recombination; loss of any of the three genes partially rescues CO-defective mutants and causes synthetic meiotic catastrophe with the pro-CO factor MUS81. Genetic screen in Arabidopsis; genetic epistasis with CO-defective and MUS81 mutants; co-immunoprecipitation/physical interaction assays Nucleic acids research Medium 36652992
2019 Wild-type p53 activates transcription of miR-30c by binding its promoter; miR-30c in turn targets FANCF (and REV1), thereby suppressing FANCF expression. In p53-mutant breast cancer cells, loss of this regulation leads to FANCF upregulation and increased adriamycin resistance. Luciferase reporter assay for p53 binding to miR-30c promoter; miR-30c overexpression/inhibition with Western blot for FANCF; adriamycin sensitivity assays in p53-WT vs mutant cell lines Cell death & disease Medium 31511498
2011 Fancf-deficient mouse embryonic fibroblasts are unable to monoubiquitinate FANCD2, show G2 arrest, chromosomal aberrations, and reduced survival in response to DNA cross-linking agents, confirming FANCF is required for FANCD2 activation in vivo. Fancf knockout mice show compromised follicle development and spermatogenesis, and increased incidence of ovarian tumors. Targeted gene disruption (knockout mouse model); Western blot for FANCD2 monoubiquitination; chromosomal aberration assay; survival assay with cross-linking agents; tumor monitoring with aCGH The Journal of pathology High 21915857

Source papers

Stage 0 corpus · 30 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 The Fanconi anemia protein FANCF forms a nuclear complex with FANCA, FANCC and FANCG. Human molecular genetics 167 11063725
2004 Promoter hypermethylation of FANCF: disruption of Fanconi Anemia-BRCA pathway in cervical cancer. Cancer research 160 15126331
2004 CpG methylation of the FHIT, FANCF, cyclin-D2, BRCA2 and RUNX3 genes in Granulosa cell tumors (GCTs) of ovarian origin. Molecular cancer 75 15574200
2007 Estrogen receptor alpha, BRCA1, and FANCF promoter methylation occur in distinct subsets of sporadic breast cancers. Breast cancer research and treatment 70 17932744
2003 FANCF methylation contributes to chemoselectivity in ovarian cancer. Cancer cell 60 12781358
2006 Promoter hypermethylation of FANCF plays an important role in the occurrence of ovarian cancer through disrupting Fanconi anemia-BRCA pathway. Cancer biology & therapy 58 16418574
2003 Bi-allelic silencing of the Fanconi anaemia gene FANCF in acute myeloid leukaemia. British journal of haematology 54 14617007
2004 The Fanconi anemia gene product FANCF is a flexible adaptor protein. The Journal of biological chemistry 53 15262960
2008 Promoter hypermethylation of FANCF and outcome in advanced ovarian cancer. British journal of cancer 41 18414472
2012 Curcumin causes promoter hypomethylation and increased expression of FANCF gene in SiHa cell line. Molecular and cellular biochemistry 37 22297615
2006 Structural determinants of human FANCF protein that function in the assembly of a DNA damage signaling complex. The Journal of biological chemistry 34 17082180
2011 Fancf-deficient mice are prone to develop ovarian tumours. The Journal of pathology 29 21915857
2019 Clinical importance of FANCD2, BRIP1, BRCA1, BRCA2 and FANCF expression in ovarian carcinomas. Cancer biology & therapy 25 30822218
2019 Intrinsic adriamycin resistance in p53-mutated breast cancer is related to the miR-30c/FANCF/REV1-mediated DNA damage response. Cell death & disease 22 31511498
2012 Gene silencing of FANCF potentiates the sensitivity to mitoxantrone through activation of JNK and p38 signal pathways in breast cancer cells. PloS one 21 22952942
2023 The FANCC-FANCE-FANCF complex is evolutionarily conserved and regulates meiotic recombination. Nucleic acids research 20 36652992
2009 The interferon consensus sequence binding protein (ICSBP/IRF8) activates transcription of the FANCF gene during myeloid differentiation. The Journal of biological chemistry 18 19801548
2017 Loss of heterozygosity in FANCG, FANCF and BRIP1 from head and neck squamous cell carcinoma of the oral cavity. International journal of oncology 12 28440438
2015 Involvement of Fanconi anemia genes FANCD2 and FANCF in the molecular basis of drug resistance in leukemia. Molecular medicine reports 12 25647473
2013 RNAi-mediated knockdown of FANCF suppresses cell proliferation, migration, invasion, and drug resistance potential of breast cancer cells. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 12 24345874
2009 Low incidence of methylation of the promoter region of the FANCF gene in Japanese primary breast cancer. Breast cancer (Tokyo, Japan) 12 19813073
2013 RNA interference-mediated FANCF silencing sensitizes OVCAR3 ovarian cancer cells to adriamycin through increased adriamycin-induced apoptosis dependent on JNK activation. Oncology reports 9 23440494
2019 A novel frame-shift deletion in FANCF gene causing autosomal recessive Fanconi anemia: a case report. BMC medical genetics 7 31288759
2015 Clinical aspects of Fanconi anemia individuals with the same mutation of FANCF identified by next generation sequencing. Birth defects research. Part A, Clinical and molecular teratology 6 26033879
2017 – (-) Menthol Induces Reversal of Promoter Hypermethylation and Associated Up-Regulation of the FANCF Gene in the SiHa Cell Line. Asian Pacific journal of cancer prevention : APJCP 5 28612587
2006 No evidence of significant silencing of Fanconi genes FANCF and FANCB or Nijmegen breakage syndrome gene NBS1 by DNA hyper-methylation in sporadic childhood leukaemia. British journal of haematology 5 16803569
2022 [Corrigendum) RNA interference‑mediated FANCF silencing sensitizes OVCAR3 ovarian cancer cells to adriamycin through increased adriamycin‑induced apoptosis dependent on JNK activation. Oncology reports 2 35543152
2022 Genetic analysis of a Fanconi anemia case revealed the presence of FANCF mutation (exon 1;469>C-T) with implications to develop acute myeloid leukemia. Molecular biology reports 2 36369330
2016 Phenotypic variability in patients with Fanconi anemia and biallelic FANCF mutations. American journal of medical genetics. Part A 2 27714961
2020 FANCF hypomethylation is associated with colorectal cancer in Han Chinese. The Turkish journal of gastroenterology : the official journal of Turkish Society of Gastroenterology 1 32915143

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