FANCF explained

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

Cancer

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

Methylation of the promoter region of the FANCF gene causes reduced expression of FANCF protein.^[16]

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%	^[17]
Cervical carcinoma	30%	^[18]
Ovarian cancer	21%-28%	^[19]
Head and neck squamous carcinomas	15%	^[20]
Non-small cell lung cancer	14%	^[21]
Male germ cell tumor	6%	^[22]

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.^[23]

Although mutations in FANCF are ordinarily not observed in human tumors, an FANCF-deficient mouse model was prone to ovarian cancers.^[24]

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. 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.

Further reading

• Maruyama K, Sugano S . Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides . Gene . 138 . 1–2 . 171–4 . January 1994 . 8125298 . 10.1016/0378-1119(94)90802-8 .
• Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, Suyama A, Sugano S . Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library . Gene . 200 . 1–2 . 149–56 . October 1997 . 9373149 . 10.1016/S0378-1119(97)00411-3 .
• de Winter JP, Rooimans MA, van Der Weel L, van Berkel CG, Alon N, Bosnoyan-Collins L, de Groot J, Zhi Y, Waisfisz Q, Pronk JC, Arwert F, Mathew CG, Scheper RJ, Hoatlin ME, Buchwald M, Joenje H . The Fanconi anaemia gene FANCF encodes a novel protein with homology to ROM . Nature Genetics . 24 . 1 . 15–6 . January 2000 . 10615118 . 10.1038/71626 . 26394122 .
• de Winter JP, van der Weel L, de Groot J, Stone S, Waisfisz Q, Arwert F, Scheper RJ, Kruyt FA, Hoatlin ME, Joenje H . The Fanconi anemia protein FANCF forms a nuclear complex with FANCA, FANCC and FANCG . Human Molecular Genetics . 9 . 18 . 2665–74 . November 2000 . 11063725 . 10.1093/hmg/9.18.2665 . free .
• Medhurst AL, Huber PA, Waisfisz Q, de Winter JP, Mathew CG . Direct interactions of the five known Fanconi anaemia proteins suggest a common functional pathway . Human Molecular Genetics . 10 . 4 . 423–9 . February 2001 . 11157805 . 10.1093/hmg/10.4.423 . free .
• Pace P, Johnson M, Tan WM, Mosedale G, Sng C, Hoatlin M, de Winter J, Joenje H, Gergely F, Patel KJ . FANCE: the link between Fanconi anaemia complex assembly and activity . The EMBO Journal . 21 . 13 . 3414–23 . July 2002 . 12093742 . 125396 . 10.1093/emboj/cdf355 .
• Taniguchi T, D'Andrea AD . The Fanconi anemia protein, FANCE, promotes the nuclear accumulation of FANCC . Blood . 100 . 7 . 2457–62 . October 2002 . 12239156 . 10.1182/blood-2002-03-0860 . 71381 .
• Gordon SM, Buchwald M . Fanconi anemia protein complex: mapping protein interactions in the yeast 2- and 3-hybrid systems . Blood . 102 . 1 . 136–41 . July 2003 . 12649160 . 10.1182/blood-2002-11-3517 .
• Meetei AR, Sechi S, Wallisch M, Yang D, Young MK, Joenje H, Hoatlin ME, Wang W . A multiprotein nuclear complex connects Fanconi anemia and Bloom syndrome . Molecular and Cellular Biology . 23 . 10 . 3417–26 . May 2003 . 12724401 . 164758 . 10.1128/MCB.23.10.3417-3426.2003 .
• 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 . A novel ubiquitin ligase is deficient in Fanconi anemia . Nature Genetics . 35 . 2 . 165–70 . October 2003 . 12973351 . 10.1038/ng1241 . 10149290 .
• Marsit CJ, Liu M, Nelson HH, Posner M, Suzuki M, Kelsey KT . Inactivation of the Fanconi anemia/BRCA pathway in lung and oral cancers: implications for treatment and survival . Oncogene . 23 . 4 . 1000–4 . January 2004 . 14647419 . 10.1038/sj.onc.1207256 . 23932665 .
• Tsutsumi S, Kamata N, Vokes TJ, Maruoka Y, Nakakuki K, Enomoto S, Omura K, Amagasa T, Nagayama M, Saito-Ohara F, Inazawa J, Moritani M, Yamaoka T, Inoue H, Itakura M . The novel gene encoding a putative transmembrane protein is mutated in gnathodiaphyseal dysplasia (GDD) . American Journal of Human Genetics . 74 . 6 . 1255–61 . June 2004 . 15124103 . 1182089 . 10.1086/421527 .
• 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 . Promoter hypermethylation of FANCF: disruption of Fanconi Anemia-BRCA pathway in cervical cancer . Cancer Research . 64 . 9 . 2994–7 . May 2004 . 15126331 . 10.1158/0008-5472.CAN-04-0245 . free .
• 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 . The Fanconi anemia gene product FANCF is a flexible adaptor protein . The Journal of Biological Chemistry . 279 . 38 . 39421–30 . September 2004 . 15262960 . 10.1074/jbc.M407034200 . free .
• Meetei AR, Levitus M, Xue Y, Medhurst AL, Zwaan M, Ling C, Rooimans MA, Bier P, Hoatlin M, Pals G, de Winter JP, Wang W, Joenje H . X-linked inheritance of Fanconi anemia complementation group B . Nature Genetics . 36 . 11 . 1219–24 . November 2004 . 15502827 . 10.1038/ng1458 . free .
• Meetei AR, Medhurst AL, Ling C, Xue Y, Singh TR, Bier P, Steltenpool J, Stone S, Dokal I, Mathew CG, Hoatlin M, Joenje H, de Winter JP, Wang W . A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M . Nature Genetics . 37 . 9 . 958–63 . September 2005 . 16116422 . 2704909 . 10.1038/ng1626 .

Notes and 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 . Evidence for at least eight Fanconi anemia genes . American Journal of Human Genetics . 61 . 4 . 940–4 . October 1997 . 9382107 . 1715980 . 10.1086/514881 .
2. Web site: Entrez Gene: FANCF Fanconi anemia, complementation group F.
3. 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 . The Fanconi anemia gene product FANCF is a flexible adaptor protein . The Journal of Biological Chemistry . 279 . 38 . 39421–30 . September 2004 . 15262960 . 10.1074/jbc.M407034200 . free .
4. de Winter JP, van der Weel L, de Groot J, Stone S, Waisfisz Q, Arwert F, Scheper RJ, Kruyt FA, Hoatlin ME, Joenje H . The Fanconi anemia protein FANCF forms a nuclear complex with FANCA, FANCC and FANCG . Human Molecular Genetics . 9 . 18 . 2665–74 . November 2000 . 11063725 . 10.1093/hmg/9.18.2665 . free .
5. Gordon SM, Buchwald M . Fanconi anemia protein complex: mapping protein interactions in the yeast 2- and 3-hybrid systems . Blood . 102 . 1 . 136–41 . July 2003 . 12649160 . 10.1182/blood-2002-11-3517 .
6. Medhurst AL, Huber PA, Waisfisz Q, de Winter JP, Mathew CG . Direct interactions of the five known Fanconi anaemia proteins suggest a common functional pathway . Human Molecular Genetics . 10 . 4 . 423–9 . February 2001 . 11157805 . 10.1093/hmg/10.4.423 . free .
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 . A novel ubiquitin ligase is deficient in Fanconi anemia . Nature Genetics . 35 . 2 . 165–70 . October 2003 . 12973351 . 10.1038/ng1241 . 10149290 .
8. Pace P, Johnson M, Tan WM, Mosedale G, Sng C, Hoatlin M, de Winter J, Joenje H, Gergely F, Patel KJ . FANCE: the link between Fanconi anaemia complex assembly and activity . The EMBO Journal . 21 . 13 . 3414–23 . July 2002 . 12093742 . 125396 . 10.1093/emboj/cdf355 .
9. Kottemann MC, Smogorzewska A . Fanconi anaemia and the repair of Watson and Crick DNA crosslinks . Nature . 493 . 7432 . 356–63 . January 2013 . 23325218 . 3700363 . 10.1038/nature11863 . 2013Natur.493..356K .
10. Pradhan A, Ustiyan V, Zhang Y, Kalin TV, Kalinichenko VV . Forkhead transcription factor FoxF1 interacts with Fanconi anemia protein complexes to promote DNA damage response . Oncotarget . 7 . 2 . 1912–26 . January 2016 . 26625197 . 10.18632/oncotarget.6422 . 4811506.
11. Kastan MB . DNA damage responses: mechanisms and roles in human disease: 2007 G.H.A. Clowes Memorial Award Lecture . Molecular Cancer Research . 6 . 4 . 517–24 . April 2008 . 18403632 . 10.1158/1541-7786.MCR-08-0020 . free .
12. Harper JW, Elledge SJ . The DNA damage response: ten years after . Molecular Cell . 28 . 5 . 739–45 . December 2007 . 18082599 . 10.1016/j.molcel.2007.11.015 . free .
13. Dietlein F, Reinhardt HC . Molecular pathways: exploiting tumor-specific molecular defects in DNA repair pathways for precision cancer therapy . Clinical Cancer Research . 20 . 23 . 5882–7 . December 2014 . 25451105 . 10.1158/1078-0432.CCR-14-1165 . 16005088 .
14. O'Hagan HM, Mohammad HP, Baylin SB . 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 . 2008 . 18704159 . 2491723 . 10.1371/journal.pgen.1000155 . free .
15. 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 . DNA damage, homology-directed repair, and DNA methylation . PLOS Genetics . 3 . 7 . e110 . July 2007 . 17616978 . 1913100 . 10.1371/journal.pgen.0030110 . free .
16. Taniguchi T, Tischkowitz M, Ameziane N, Hodgson SV, Mathew CG, Joenje H, Mok SC, D'Andrea AD . Disruption of the Fanconi anemia-BRCA pathway in cisplatin-sensitive ovarian tumors . Nature Medicine . 9 . 5 . 568–74 . May 2003 . 12692539 . 10.1038/nm852 . 22912496 .
17. Ding JJ, Wang G, Shi WX, Zhou HH, Zhao EF . Promoter Hypermethylation of FANCF and Susceptibility and Prognosis of Epithelial Ovarian Cancer . Reproductive Sciences . 23 . 1 . 24–30 . January 2016 . 26507869 . 10.1177/1933719115612136 . 21461736 . free .
18. 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 . Promoter hypermethylation of FANCF: disruption of Fanconi Anemia-BRCA pathway in cervical cancer . Cancer Research . 64 . 9 . 2994–7 . May 2004 . 15126331 . 10.1158/0008-5472.can-04-0245. free .
19. Wang Z, Li M, Lu S, Zhang Y, Wang H . 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 . March 2006 . 16418574 . 10.4161/cbt.5.3.2380. free .
20. Marsit CJ, Liu M, Nelson HH, Posner M, Suzuki M, Kelsey KT . Inactivation of the Fanconi anemia/BRCA pathway in lung and oral cancers: implications for treatment and survival . Oncogene . 23 . 4 . 1000–4 . January 2004 . 14647419 . 10.1038/sj.onc.1207256 . 23932665 .
21. Guo M, Alumkal J, Drachova T, Gao D, Marina SS, Jen J, Herman JG . 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 . March 2015 . 25828518 .
22. Koul S, McKiernan JM, Narayan G, Houldsworth J, Bacik J, Dobrzynski DL, Assaad AM, Mansukhani M, Reuter VE, Bosl GJ, Chaganti RS, Murty VV . Role of promoter hypermethylation in Cisplatin treatment response of male germ cell tumors . Molecular Cancer . 3 . 16 . May 2004 . 15149548 . 420487 . 10.1186/1476-4598-3-16 . free .
23. Volinia S, Galasso M, Sana ME, Wise TF, Palatini J, Huebner K, Croce CM . 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 . February 2012 . 22315424 . 3286983 . 10.1073/pnas.1200010109 . 2012PNAS..109.3024V . free .
24. 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 . Fancf-deficient mice are prone to develop ovarian tumours . The Journal of Pathology . 226 . 1 . 28–39 . January 2012 . 21915857 . 10.1002/path.2992 . 26239010 .