FANCF

FANCF
Dostupne strukture PDB Pretraga ortologa: PDBe RCSB Spisak PDB ID kodova 2IQC
Identifikatori
Aliasi	FANCF
Vanjski ID-jevi	OMIM: 613897 MGI: 3689889 HomoloGene: 75185 GeneCards: FANCF
Lokacija gena (čovjek) Hrom. Hromosom 11 (čovjek)[1] Bend 11p14.3 Početak 22,622,533 bp[1] Kraj 22,625,823 bp[1]
Lokacija gena (miš) Hrom. Hromosom 7 (miš)[2] Bend 7|7 B4 Početak 51,510,325 bp[2] Kraj 51,512,015 bp[2]
Obrazac RNK ekspresije Više referentnih podataka o ekspresiji
Ontologija gena Molekularna funkcija • GO:0001948, GO:0016582 vezivanje za proteine • molekularna funkcija • GO:1904264, GO:1904822, GO:0090622, GO:0090302 ubiquitin protein ligase activity Ćelijska komponenta • Fanconi anaemia nuclear complex • jedro • nukleoplazma Biološki proces • interstrand cross-link repair • cellular response to DNA damage stimulus • GO:0100026 Popravka DNK • GO:0022610 biološki proces • ovarian follicle development • Spermatogeneza • protein ubiquitination Izvori:Amigo / QuickGO
Ortolozi
Vrste	Čovjek	Miš
Entrez	2188	100040608
Ensembl	ENSG00000183161	ENSMUSG00000092118
UniProt	Q9NPI8	E9Q5Z5
RefSeq (mRNK)	NM_022725	NM_001115087
RefSeq (bjelančevina)	NP_073562	NP_001108559
Lokacija (UCSC)	Chr 11: 22.62 – 22.63 Mb	Chr 7: 51.51 – 51.51 Mb
PubMed pretraga	[3]	[4]
Wikipodaci
Pogledaj/uredi – čovjek Pogledaj/uredi – miš

Proteinska grupa F Fanconijeve anemije jest protein koji je kod ljudi kodiran genom FANCF sa hromosoma 11.^[5][6]

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 374 aminokiseline, a molekulska težina 42.254 Da.^[6]

• C: Cistein
• D: Asparaginska kiselina
• E: Glutaminska kiselina
• F: Fenilalanin
• G: Glicin
• H: Histidin
• I: Izoleucin
• K: Lizin
• L: Leucin
• M: Metionin
• N: Asparagin
• P: Prolin
• Q: Glutamin
• R: Arginin
• S: Serin
• T: Treonin
• V: Valin
• W: Triptofan
• Y: Tirozin

10		20		30		40		50
MESLLQHLDR		FSELLAVSST		TYVSTWDPAT		VRRALQWARY		LRHIHRRFGR
HGPIRTALER		RLHNQWRQEG		GFGRGPVPGL		ANFQALGHCD		VLLSLRLLEN
RALGDAARYH		LVQQLFPGPG		VRDADEETLQ		ESLARLARRR		SAVHMLRFNG
YRENPNLQED		SLMKTQAELL		LERLQEVGKA		EAERPARFLS		SLWERLPQNN
FLKVIAVALL		QPPLSRRPQE		ELEPGIHKSP		GEGSQVLVHW		LLGNSEVFAA
FCRALPAGLL		TLVTSRHPAL		SPVYLGLLTD		WGQRLHYDLQ		KGIWVGTESQ
DVPWEELHNR		FQSLCQAPPP		LKDKVLTALE		TCKAQDGDFE		VPGLSIWTDL
LLALRSGAFR		KRQVLGLSAG		LSSV

Funkcija

FANCF je adapterski protein koji ima ključnu ulogu u pravilnom sklapanju kompleksa jezgra FA.^[7] Kompleks jezgre FA sastoji se od osam proteina (FANCA, FANCB, -FANCC, FANCE, FANCF, FANCG, FANCL i FANCM).^[8][9] FANCF stabilizira interakciju između potkompleksa FANCC/FANCE i potkompleksa FANCA/FANCG i zaključava cijeli kompleks jezgra FA u konformaciju koja je neophodna za obavljanje svoje funkcije u popravci DNK.^[7]

Kompleks jezgra FA je kompleks jedarnog jezgra koji je neophodan za monoubikvitinaciju FANCD2 i ovaj modifikovani oblik FANCD2 kolokalizuje se sa BRCA1, RAD51 i PCNA u fokusima koji također sadrže druge proteine za popravku DNK.^[7] Sve ovi proteini funkcionišu zajedno kako bi olakšali popravku umrežene veze između DNK. Također funkcionišu u drugim procesima popravke odgovora na oštećenje DNK, uključujući oporavak i stabilizaciju zaustavljenih replikacijskih viljuški.^[9] FoxF1 protein također stupa u interakciju sa jezgrom FA proteina i inducira njegovo vezivanje za hromatin, kako bi promovirao popravak DNK.^[9]

Kancer

Čini se da je oštećenje DNK primarni uzrok raka,^[10] a čini se da su nedostaci u ekspresiji gena za popravku DNK u osnovi mnogih oblika raka[].^[11][12] Ako je popravak DNK nedovoljan, oštećenje DNK ima tendenciju da se akumulira. Takvo prekomjerno oštećenje DNK može povećati mutacije zbog sklonosti greškama translezijske sinteze. Prekomjerno oštećenje DNK također može povećati epigenetičke promjene zbog grešaka tokom popravke DNK.^[13][14] Takve mutacije i epigenetske promjene mogu dovesti do raka.

Smanjenje ekspresija gena za popravku DNK (obično uzrokovano epigenetičkim promjenama) vrlo je uobičajeno kod karcinoma, i najčešće je mnogo češće od mutacijskih defekata u genima za popravku DNK kod karcinoma.

Metilacija promotorske regije gena FANCF uzrokuje smanjenu ekspresiju proteina FANCF.^[15]

Učestalosti metilacije promotora FANCF u nekoliko različitih karcinoma prikazane su u tabeli.

Frekvencija metilacije promotora FANCF kod sporadičnih karcinoma

Kancer	Učestalost	Referenca
Epitelni rak jajnika	32%	[16]
Rak grlića maternice	30%	[17]
Rak jajnika	21%-28%	[15][18]
Skvamozni karcinom glave i vrata	15%	[19]
Rak pluća nemalih ćelija	14%	[19][20]
Tumor muških germinativnih ćelija	6%	[21]

Kod invazivnih karcinoma dojke, mikroRNK-210 (miR-210) je povećana, zajedno sa smanjenom ekspresijom FANCF, gdje je FANCF bio jedna od vjerojatnih meta miR-210.^[22]

Iako se mutacije u "FANCF" obično ne primjećuju u ljudskim tumorima, mišji model s nedostatkom "FANCF" bio je sklon raku jajnika.^[23]

Čini se da je FANCF jedan od oko 26 gena za popravku DNK koji su epigenetski potisnuti kod različitih karcinoma (vidi Epigenetika raka).

Neplodnost

Gonadni FANCF mutantnih miševa funkcionišu abnormalno, kompromitujući razvoj folikula i spermatogenezu kao što je uočeno na drugim modelima mišje Fanconijeve anemije i Fanconijevom anemijom pacijenata.^[23] Histološki pregled testisa kod miševa s nedostatkom FANCF-a pokazao je da su seminferni tubuli lišeni klicnih ćelija. U dobi od 14 sedmica, ženke miševa s nedostatkom FANCF-a bile su gotovo ili potpuno lišene primordijalnih folikula. Zaključeno je da miševi s nedostatkom FANCF-a pokazuju brzo iscrpljivanje primordijalnih folikula u mladoj dobi, što rezultira uznapredovalim jajnika.^[23]

Interakcije

Pokazalo se da FANCF reaguje sa FANCA,^[7][24] FANCG,^{[7][24][25][26]} FANCA^[7][24][27] i FANCE.^[7][28]

Reference

1. GRCh38: Ensembl release 89: ENSG00000183161 - Ensembl, maj 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000092118 - Ensembl, maj 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 (oktobar 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. 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 (septembar 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. Kottemann MC, Smogorzewska A (januar 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.
9. Pradhan A, Ustiyan V, Zhang Y, Kalin TV, Kalinichenko VV (januar 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.
10. 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.
11. Harper JW, Elledge SJ (decembar 2007). "The DNA damage response: ten years after". Molecular Cell. 28 (5): 739–45. doi:10.1016/j.molcel.2007.11.015. PMID 18082599.
12. Dietlein F, Reinhardt HC (decembar 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.
13. 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.
14. 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 (juli 2007). "DNA damage, homology-directed repair, and DNA methylation". PLOS Genetics. 3 (7): e110. doi:10.1371/journal.pgen.0030110. PMC 1913100. PMID 17616978.
15. Taniguchi T, Tischkowitz M, Ameziane N, Hodgson SV, Mathew CG, Joenje H, Mok SC, D'Andrea AD (maj 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.
16. Ding JJ, Wang G, Shi WX, Zhou HH, Zhao EF (januar 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.
17. 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 (maj 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.
18. Wang Z, Li M, Lu S, Zhang Y, Wang H (mart 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.
19. Marsit CJ, Liu M, Nelson HH, Posner M, Suzuki M, Kelsey KT (januar 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.
20. Guo M, Alumkal J, Drachova T, Gao D, Marina SS, Jen J, Herman JG (mart 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.
21. Koul S, McKiernan JM, Narayan G, Houldsworth J, Bacik J, Dobrzynski DL, Assaad AM, Mansukhani M, Reuter VE, Bosl GJ, Chaganti RS, Murty VV (maj 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.
22. Volinia S, Galasso M, Sana ME, Wise TF, Palatini J, Huebner K, Croce CM (februar 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.
23. 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 (januar 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.
24. de Winter JP, van der Weel L, de Groot J, Stone S, Waisfisz Q, Arwert F, Scheper RJ, Kruyt FA, Hoatlin ME, Joenje H (novembar 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.
25. Gordon SM, Buchwald M (juli 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.
26. Medhurst AL, Huber PA, Waisfisz Q, de Winter JP, Mathew CG (februar 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.
27. 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 (oktobar 2003). "A novel ubiquitin ligase is deficient in Fanconi anemia". Nature Genetics. 35 (2): 165–70. doi:10.1038/ng1241. PMID 12973351. S2CID 10149290.
28. Pace P, Johnson M, Tan WM, Mosedale G, Sng C, Hoatlin M, de Winter J, Joenje H, Gergely F, Patel KJ (juli 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.

Dopunska literatura

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• 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 (januar 2000). "The Fanconi anaemia gene FANCF encodes a novel protein with homology to ROM". Nature Genetics. 24 (1): 15–6. doi:10.1038/71626. PMID 10615118. S2CID 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 (novembar 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.
• Medhurst AL, Huber PA, Waisfisz Q, de Winter JP, Mathew CG (februar 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.
• Pace P, Johnson M, Tan WM, Mosedale G, Sng C, Hoatlin M, de Winter J, Joenje H, Gergely F, Patel KJ (juli 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.
• Taniguchi T, D'Andrea AD (oktobar 2002). "The Fanconi anemia protein, FANCE, promotes the nuclear accumulation of FANCC". Blood. 100 (7): 2457–62. doi:10.1182/blood-2002-03-0860. PMID 12239156.
• Gordon SM, Buchwald M (juli 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.
• Meetei AR, Sechi S, Wallisch M, Yang D, Young MK, Joenje H, Hoatlin ME, Wang W (maj 2003). "A multiprotein nuclear complex connects Fanconi anemia and Bloom syndrome". Molecular and Cellular Biology. 23 (10): 3417–26. doi:10.1128/MCB.23.10.3417-3426.2003. PMC 164758. PMID 12724401.
• 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 (oktobar 2003). "A novel ubiquitin ligase is deficient in Fanconi anemia". Nature Genetics. 35 (2): 165–70. doi:10.1038/ng1241. PMID 12973351. S2CID 10149290.
• Marsit CJ, Liu M, Nelson HH, Posner M, Suzuki M, Kelsey KT (januar 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.
• 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 (juni 2004). "The novel gene encoding a putative transmembrane protein is mutated in gnathodiaphyseal dysplasia (GDD)". American Journal of Human Genetics. 74 (6): 1255–61. doi:10.1086/421527. PMC 1182089. PMID 15124103.
• 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 (maj 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.
• 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 (septembar 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.
• 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 (novembar 2004). "X-linked inheritance of Fanconi anemia complementation group B". Nature Genetics. 36 (11): 1219–24. doi:10.1038/ng1458. PMID 15502827.
• 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 (septembar 2005). "A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M". Nature Genetics. 37 (9): 958–63. doi:10.1038/ng1626. PMC 2704909. PMID 16116422.

Vanjski linkovi