FANCF

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
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Fanconi anemia group F protein is a protein that in humans is encoded by the FANCF gene.[1][2]

Interactions

FANCF has been shown to interact with Fanconi anemia, complementation group C,[3][4] FANCG,[3][4][5][6] FANCA[3][4][7] and FANCE.[3][8]

Function

FANCF is an adaptor protein that plays a key role in the proper assembly of the FA core complex.[3] The FA core complex is composed of eight proteins (FANCA, -B, -C, -E, -F, -G, -L and -M).[9][10] 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.[3]

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.[3] 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.[10] FoxF1 protein also interacts with the FA protein core and induces its binding to chromatin to promote DNA repair.[10]

Cancer

DNA damage appears to be the primary underlying cause of cancer,[11][12] and deficiencies in expression of DNA repair genes appear to underlie many forms of cancer.[13][14] 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.[15][16] 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.[17] (Also see Frequencies of epimutations in DNA repair genes.)

Methylation of the promoter region of the FANCF gene causes reduced expression of FANCF protein.[18]

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

Frequency of FANCF promoter methylation in sporadic cancers
Cancer Frequency Ref.
Epithelian ovarian cancer 32% [19]
Cervical carcinoma 30% [20]
Ovarian cancer 21%-28% [18][21]
Head and neck squamous carcinomas 15% [22]
Non-small cell lung cancer 14% [22][23]
Male germ cell tumor 6% [24]

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.[25]

Although mutations in FANCF are ordinarily not observed in human tumors, an FANCF-deficient mouse model was prone to ovarian cancers.[26]

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.[26] 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.[26]

References

  1. ↑ 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.
  2. ↑ "Entrez Gene: FANCF Fanconi anemia, complementation group F".
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 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.
  4. ↑ 4.0 4.1 4.2 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.
  5. ↑ Gordon SM, Buchwald M (July 2003). "Fanconi anemia protein complex: mapping protein interactions in the yeast 2- and 3-hybrid systems". Blood. 102 (1): 136–41. doi:10.1182/blood-2002-11-3517. PMID 12649160.
  6. ↑ Medhurst AL, Huber PA, Waisfisz Q, de Winter JP, Mathew CG (February 2001). "Direct interactions of the five known Fanconi anaemia proteins suggest a common functional pathway". Human Molecular Genetics. 10 (4): 423–9. doi:10.1093/hmg/10.4.423. PMID 11157805.
  7. ↑ Meetei AR, de Winter JP, Medhurst AL, Wallisch M, Waisfisz Q, van de Vrugt HJ, Oostra AB, Yan Z, Ling C, Bishop CE, Hoatlin ME, Joenje H, Wang W (October 2003). "A novel ubiquitin ligase is deficient in Fanconi anemia". Nature Genetics. 35 (2): 165–70. doi:10.1038/ng1241. PMID 12973351.
  8. ↑ 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.
  9. ↑ Kottemann MC, Smogorzewska A (January 2013). "Fanconi anaemia and the repair of Watson and Crick DNA crosslinks". Nature. 493 (7432): 356–63. doi:10.1038/nature11863. PMC 3700363. PMID 23325218.
  10. ↑ 10.0 10.1 10.2 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.
  11. ↑ 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.
  12. ↑ Bernstein C, Prasad AR, Nfonsam V, Bernstein H (2013). "DNA Damage, DNA Repair and Cancer, New Research Directions in DNA Repair". In Chen C. Biochemistry, Genetics and Molecular Biology. InTech. ISBN 978-953-51-1114-6.
  13. ↑ Harper JW, Elledge SJ (December 2007). "The DNA damage response: ten years after". Molecular Cell. 28 (5): 739–45. doi:10.1016/j.molcel.2007.11.015. PMID 18082599.
  14. ↑ Dietlein F, Reinhardt HC (December 2014). "Molecular pathways: exploiting tumor-specific molecular defects in DNA repair pathways for precision cancer therapy". Clinical Cancer Research. 20 (23): 5882–7. doi:10.1158/1078-0432.CCR-14-1165. PMID 25451105.
  15. ↑ O'Hagan HM, Mohammad HP, Baylin SB (2008). "Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island". PLoS Genetics. 4 (8): e1000155. doi:10.1371/journal.pgen.1000155. PMC 2491723. PMID 18704159.
  16. ↑ Cuozzo C, Porcellini A, Angrisano T, Morano A, Lee B, Di Pardo A, Messina S, Iuliano R, Fusco A, Santillo MR, Muller MT, Chiariotti L, Gottesman ME, Avvedimento EV (July 2007). "DNA damage, homology-directed repair, and DNA methylation". PLoS Genetics. 3 (7): e110. doi:10.1371/journal.pgen.0030110. PMC 1913100. PMID 17616978.
  17. ↑ Carol Bernstein and Harris Bernstein (2015). Epigenetic Reduction of DNA Repair in Progression to Cancer, Advances in DNA Repair, Prof. Clark Chen (Ed.), ISBN 978-953-51-2209-8, InTech, Available from: http://www.intechopen.com/books/advances-in-dna-repair/epigenetic-reduction-of-dna-repair-in-progression-to-cancer
  18. ↑ 18.0 18.1 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.
  19. ↑ 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.
  20. ↑ Narayan G, Arias-Pulido H, Nandula SV, Basso K, Sugirtharaj DD, Vargas H, Mansukhani M, Villella J, Meyer L, Schneider A, Gissmann L, Dürst M, Pothuri B, Murty VV (May 2004). "Promoter hypermethylation of FANCF: disruption of Fanconi Anemia-BRCA pathway in cervical cancer". Cancer Research. 64 (9): 2994–7. doi:10.1158/0008-5472.can-04-0245. PMID 15126331.
  21. ↑ 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.
  22. ↑ 22.0 22.1 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.
  23. ↑ 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.
  24. ↑ 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.
  25. ↑ 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. doi:10.1073/pnas.1200010109. PMC 3286983. PMID 22315424.
  26. ↑ 26.0 26.1 26.2 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.

Further reading

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