FANCF
Proteinska grupa F Fanconijeve anemije jest protein koji je kod ljudi kodiran genom FANCF sa hromosoma 11.[5][6]
Aminokiselinska sekvenca uredi
Dužina polipeptidnog lanca je 374 aminokiseline, a molekulska težina 42.254 Da.[6]
| 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 uredi
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 uredi
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.
| 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 uredi
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 uredi
Pokazalo se da FANCF reaguje sa FANCA,[7][24] FANCG,[7][24][25][26] FANCA[7][24][27] i FANCE.[7][28]
Reference uredi
- ^ a b c GRCh38: Ensembl release 89: ENSG00000183161 - Ensembl, maj 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000092118 - Ensembl, maj 2017
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- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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- ^ a b "Entrez Gene: FANCF Fanconi anemia, complementation group F".
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- ^ 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.
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- ^ 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.
- ^ 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.
- ^ a b 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.
- ^ 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.
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- ^ a b c 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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 uredi
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