FANCF

Last updated
FANCF
Protein FANCF PDB 2iqc.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases FANCF , FAF, Fanconi anemia complementation group F, FA complementation group F
External IDs OMIM: 613897 MGI: 3689889 HomoloGene: 75185 GeneCards: FANCF
Orthologs
SpeciesHumanMouse
Entrez

2188

100040608

Ensembl

ENSG00000183161

ENSMUSG00000092118

UniProt

Q9NPI8

E9Q5Z5

RefSeq (mRNA)

NM_022725

NM_001115087

RefSeq (protein)

NP_073562

NP_001108559

Location (UCSC) Chr 11: 22.62 – 22.63 Mb Chr 7: 51.51 – 51.51 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Fanconi anemia group F protein is a protein that in humans is encoded by the FANCF gene. [5] [6]

Contents

Interactions

FANCF has been shown to interact with Fanconi anemia, complementation group C, [7] [8] FANCG, [7] [8] [9] [10] FANCA [7] [8] [11] and FANCE. [7] [12]

Function

FANCF is an adaptor protein that plays a key role in the proper assembly of the FA core complex. [7] The FA core complex is composed of eight proteins (FANCA, -B, -C, -E, -F, -G, -L and -M). [13] [14] FANCF stabilizes the interaction between the FANCC/FANCE subcomplex and the FANCA/FANCG subcomplex and locks the whole FA core complex in a conformation that is essential to perform its function in DNA repair. [7]

The FA core complex is a nuclear core complex that is essential for the monoubiquitination of FANCD2 and this modified form of FANCD2 colocalizes with BRCA1, RAD51 and PCNA in foci that also contain other DNA repair proteins. [7] All these proteins function together to facilitate DNA interstrand cross-link repair. They also function in other DNA damage response repair processes including recovering and stabilizing stalled replication forks. [14] FoxF1 protein also interacts with the FA protein core and induces its binding to chromatin to promote DNA repair. [14]

Cancer

DNA damage appears to be the primary underlying cause of cancer, [15] and deficiencies in expression of DNA repair genes appear to underlie many forms of cancer. [16] [17] If DNA repair is deficient, DNA damage tends to accumulate. Such excess DNA damage may increase mutations due to error-prone translesion synthesis. Excess DNA damage may also increase epigenetic alterations due to errors during DNA repair. [18] [19] Such mutations and epigenetic alterations may give rise to cancer.

Reductions in expression of DNA repair genes (usually caused by epigenetic alterations) are very common in cancers, and are most often much more frequent than mutational defects in DNA repair genes in cancers.[ citation needed ] (Also see Frequencies of epimutations in DNA repair genes.)

Methylation of the promoter region of the FANCF gene causes reduced expression of FANCF protein. [20]

The frequencies of FANCF promoter methylation in several different cancers is indicated in the table.

Frequency of FANCF promoter methylation in sporadic cancers
CancerFrequencyRef.
Epithelian ovarian cancer32% [21]
Cervical carcinoma30% [22]
Ovarian cancer21%-28% [20] [23]
Head and neck squamous carcinomas15% [24]
Non-small cell lung cancer14% [24] [25]
Male germ cell tumor6% [26]

In invasive breast cancers, microRNA-210 (miR-210) was increased, along with decreased expression of FANCF, where FANCF was one of the likely targets of miR-210. [27]

Although mutations in FANCF are ordinarily not observed in human tumors, an FANCF-deficient mouse model was prone to ovarian cancers. [28]

FANCF appears to be one of about 26 DNA repair genes that are epigenetically repressed in various cancers (see Cancer epigenetics).

Infertility

The gonads of FANCF mutant mice function abnormally, having compromised follicle development and spermatogenesis as has been observed in other Fanconi anemia mouse models and in Fanconi anemia patients. [28] Histological examination of the testes from FANCF-deficient mice showed that the seminiferous tubules were devoid of germ cells. At 14 weeks of age, FANCF-deficient female mice were almost or completely devoid of primordial follicles. It was concluded that FANCF-deficient mice display a rapid depletion of primordial follicles at a young age resulting in advanced ovarian aging. [28]

Related Research Articles

<span class="mw-page-title-main">BRCA1</span> Gene known for its role in breast cancer

Breast cancer type 1 susceptibility protein is a protein that in humans is encoded by the BRCA1 gene. Orthologs are common in other vertebrate species, whereas invertebrate genomes may encode a more distantly related gene. BRCA1 is a human tumor suppressor gene and is responsible for repairing DNA.

<span class="mw-page-title-main">Fanconi anemia</span> Medical condition

Fanconi anemia (FA) is a rare, AR, genetic disease resulting in impaired response to DNA damage in the FA/BRCA pathway. Although it is a very rare disorder, study of this and other bone marrow failure syndromes has improved scientific understanding of the mechanisms of normal bone marrow function and development of cancer. Among those affected, the majority develop cancer, most often acute myelogenous leukemia (AML), MDS, and liver tumors. 90% develop aplastic anemia by age 40. About 60–75% have congenital defects, commonly short stature, abnormalities of the skin, arms, head, eyes, kidneys, and ears, and developmental disabilities. Around 75% have some form of endocrine problem, with varying degrees of severity. 60% of FA is FANC-A, 16q24.3, which has later onset bone marrow failure.

<span class="mw-page-title-main">GSTP1</span> Protein-coding gene in the species Homo sapiens

Glutathione S-transferase P is an enzyme that in humans is encoded by the GSTP1 gene.

<span class="mw-page-title-main">Fanconi anemia, complementation group C</span> Protein-coding gene in the species Homo sapiens

Fanconi anemia group C protein is a protein that in humans is encoded by the FANCC gene. This protein delays the onset of apoptosis and promotes homologous recombination repair of damaged DNA. Mutations in this gene result in Fanconi anemia, a human rare disorder characterized by cancer susceptibility and cellular sensitivity to DNA crosslinks and other damages.

<span class="mw-page-title-main">FANCA</span> Protein-coding gene in the species Homo sapiens

Fanconi anaemia, complementation group A, also known as FAA, FACA and FANCA, is a protein which in humans is encoded by the FANCA gene. It belongs to the Fanconi anaemia complementation group (FANC) family of genes of which 12 complementation groups are currently recognized and is hypothesised to operate as a post-replication repair or a cell cycle checkpoint. FANCA proteins are involved in inter-strand DNA cross-link repair and in the maintenance of normal chromosome stability that regulates the differentiation of haematopoietic stem cells into mature blood cells.

<span class="mw-page-title-main">FANCD2</span> Protein-coding gene in the species Homo sapiens

Fanconi anemia group D2 protein is a protein that in humans is encoded by the FANCD2 gene. The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ, FANCL, FANCM, FANCN and FANCO.

<span class="mw-page-title-main">FANCG</span> Protein-coding gene in the species Homo sapiens

Fanconi anemia group G protein is a protein that in humans is encoded by the FANCG gene.

<span class="mw-page-title-main">FANCE</span> Protein-coding gene in the species Homo sapiens

Fanconi anemia, complementation group E protein is a protein that in humans is encoded by the FANCE gene. The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, and FANCL. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA cross-linking 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 groufcrp E.

<span class="mw-page-title-main">FANCL</span> Protein-coding gene in the species Homo sapiens

E3 ubiquitin-protein ligase FANCL is an enzyme that in humans is encoded by the FANCL gene.

<span class="mw-page-title-main">FANCB</span> Protein-coding gene in the species Homo sapiens

Fanconi anemia group B protein is a protein that in humans is encoded by the FANCB gene.

<span class="mw-page-title-main">FANCI</span> Protein-coding gene in the species Homo sapiens

Fanconi anemia, complementation group I (FANCI) also known as KIAA1794, is a protein which in humans is encoded by the FANCI gene. Mutations in the FANCI gene are known to cause Fanconi anemia.

<span class="mw-page-title-main">PALB2</span> Protein-coding gene in the species Homo sapiens

Partner and localizer of BRCA2, also known as PALB2 or FANCN, is a protein which in humans is encoded by the PALB2 gene.

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Ubiquitin-specific protease 14 is an enzyme that in humans is encoded by the USP14 gene.

<span class="mw-page-title-main">RMI1</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">FANCM</span> Mammalian protein found in Homo sapiens

Fanconi anemia, complementation group M, also known as FANCM is a human gene. It is an emerging target in cancer therapy, in particular cancers with specific genetic deficiencies.

FANC proteins are a network of at least 15 proteins that are associated with a cell process known as the Fanconi anemia.

Alan D. D'Andrea is an American cancer researcher and the Fuller American Cancer Society Professor of Radiation Oncology at Harvard Medical School. D'Andrea's research at the Dana Farber Cancer Institute focuses on chromosome instability and cancer susceptibility. He is currently the director of the Center for DNA Damage and Repair and the director of the Susan F. Smith Center for Women's Cancer.

<span class="mw-page-title-main">Hereditary cancer syndrome</span> Inherited genetic condition that predisposes a person to cancer

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<span class="mw-page-title-main">Ketan J. Patel</span>

Ketan Jayakrishna Patel is a British-Kenyan scientist who is Director of the MRC Weatherall Institute of Molecular Medicine and the MRC Molecular Haematology Unit at the University of Oxford. Until 2020 he was a tenured principal investigator at the Medical Research Council (MRC) Laboratory of Molecular Biology (LMB).

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000183161 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000092118 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Joenje H, Oostra AB, Wijker M, di Summa FM, van Berkel CG, Rooimans MA, Ebell W, van Weel M, Pronk JC, Buchwald M, Arwert F (October 1997). "Evidence for at least eight Fanconi anemia genes". American Journal of Human Genetics. 61 (4): 940–4. doi:10.1086/514881. PMC   1715980 . PMID   9382107.
  6. ↑ "Entrez Gene: FANCF Fanconi anemia, complementation group F".
  7. 1 2 3 4 5 6 7 Léveillé F, Blom E, Medhurst AL, Bier P, Laghmani el H, Johnson M, Rooimans MA, Sobeck A, Waisfisz Q, Arwert F, Patel KJ, Hoatlin ME, Joenje H, de Winter JP (September 2004). "The Fanconi anemia gene product FANCF is a flexible adaptor protein". The Journal of Biological Chemistry. 279 (38): 39421–30. doi: 10.1074/jbc.M407034200 . PMID   15262960.
  8. 1 2 3 de Winter JP, van der Weel L, de Groot J, Stone S, Waisfisz Q, Arwert F, Scheper RJ, Kruyt FA, Hoatlin ME, Joenje H (November 2000). "The Fanconi anemia protein FANCF forms a nuclear complex with FANCA, FANCC and FANCG". Human Molecular Genetics. 9 (18): 2665–74. doi: 10.1093/hmg/9.18.2665 . PMID   11063725.
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  12. ↑ Pace P, Johnson M, Tan WM, Mosedale G, Sng C, Hoatlin M, de Winter J, Joenje H, Gergely F, Patel KJ (July 2002). "FANCE: the link between Fanconi anaemia complex assembly and activity". The EMBO Journal. 21 (13): 3414–23. doi:10.1093/emboj/cdf355. PMC   125396 . PMID   12093742.
  13. ↑ Kottemann MC, Smogorzewska A (January 2013). "Fanconi anaemia and the repair of Watson and Crick DNA crosslinks". Nature. 493 (7432): 356–63. Bibcode:2013Natur.493..356K. doi:10.1038/nature11863. PMC   3700363 . PMID   23325218.
  14. 1 2 3 Pradhan A, Ustiyan V, Zhang Y, Kalin TV, Kalinichenko VV (January 2016). "Forkhead transcription factor FoxF1 interacts with Fanconi anemia protein complexes to promote DNA damage response". Oncotarget. 7 (2): 1912–26. doi:10.18632/oncotarget.6422. PMC   4811506 . PMID   26625197.
  15. ↑ Kastan MB (April 2008). "DNA damage responses: mechanisms and roles in human disease: 2007 G.H.A. Clowes Memorial Award Lecture". Molecular Cancer Research. 6 (4): 517–24. doi: 10.1158/1541-7786.MCR-08-0020 . PMID   18403632.
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  20. 1 2 Taniguchi T, Tischkowitz M, Ameziane N, Hodgson SV, Mathew CG, Joenje H, Mok SC, D'Andrea AD (May 2003). "Disruption of the Fanconi anemia-BRCA pathway in cisplatin-sensitive ovarian tumors". Nature Medicine. 9 (5): 568–74. doi:10.1038/nm852. PMID   12692539. S2CID   22912496.
  21. ↑ Ding JJ, Wang G, Shi WX, Zhou HH, Zhao EF (January 2016). "Promoter Hypermethylation of FANCF and Susceptibility and Prognosis of Epithelial Ovarian Cancer". Reproductive Sciences. 23 (1): 24–30. doi: 10.1177/1933719115612136 . PMID   26507869. S2CID   21461736.
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  23. ↑ Wang Z, Li M, Lu S, Zhang Y, Wang H (March 2006). "Promoter hypermethylation of FANCF plays an important role in the occurrence of ovarian cancer through disrupting Fanconi anemia-BRCA pathway". Cancer Biology & Therapy. 5 (3): 256–60. doi: 10.4161/cbt.5.3.2380 . PMID   16418574.
  24. 1 2 Marsit CJ, Liu M, Nelson HH, Posner M, Suzuki M, Kelsey KT (January 2004). "Inactivation of the Fanconi anemia/BRCA pathway in lung and oral cancers: implications for treatment and survival". Oncogene. 23 (4): 1000–4. doi:10.1038/sj.onc.1207256. PMID   14647419. S2CID   23932665.
  25. ↑ Guo M, Alumkal J, Drachova T, Gao D, Marina SS, Jen J, Herman JG (March 2015). "CHFR methylation strongly correlates with methylation of DNA damage repair and apoptotic pathway genes in non-small cell lung cancer". Discovery Medicine. 19 (104): 151–8. PMID   25828518.
  26. ↑ Koul S, McKiernan JM, Narayan G, Houldsworth J, Bacik J, Dobrzynski DL, Assaad AM, Mansukhani M, Reuter VE, Bosl GJ, Chaganti RS, Murty VV (May 2004). "Role of promoter hypermethylation in Cisplatin treatment response of male germ cell tumors". Molecular Cancer. 3: 16. doi: 10.1186/1476-4598-3-16 . PMC   420487 . PMID   15149548.
  27. ↑ Volinia S, Galasso M, Sana ME, Wise TF, Palatini J, Huebner K, Croce CM (February 2012). "Breast cancer signatures for invasiveness and prognosis defined by deep sequencing of microRNA". Proceedings of the National Academy of Sciences of the United States of America. 109 (8): 3024–9. Bibcode:2012PNAS..109.3024V. doi: 10.1073/pnas.1200010109 . PMC   3286983 . PMID   22315424.
  28. 1 2 3 Bakker ST, van de Vrugt HJ, Visser JA, Delzenne-Goette E, van der Wal A, Berns MA, van de Ven M, Oostra AB, de Vries S, Kramer P, Arwert F, van der Valk M, de Winter JP, te Riele H (January 2012). "Fancf-deficient mice are prone to develop ovarian tumours". The Journal of Pathology. 226 (1): 28–39. doi:10.1002/path.2992. PMID   21915857. S2CID   26239010.

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