FANCL

FANCL
Dostupne strukture
PDB	Pretraga ortologa: PDBe RCSB
Spisak PDB ID kodova
	3ZQS, 4CCG
Identifikatori
Aliasi	FANCL
Vanjski ID-jevi	OMIM: 608111 MGI: 1914280 HomoloGene: 9987 GeneCards: FANCL
Lokacija gena (čovjek)
Hrom.	Hromosom 2 (čovjek)
Kraj	58,241,410 bp
Lokacija gena (miš)
Hrom.	Hromosom 11 (miš)
Kraj	26,421,876 bp
Obrazac RNK ekspresije
	Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija	• GO:0050372 aktivnost sa transferazom ubikvitina; • GO:0001948, GO:0016582 vezivanje za proteine; • vezivanje iona metala; • ubiquitin protein ligase binding; • GO:1904264, GO:1904822, GO:0090622, GO:0090302 ubiquitin protein ligase activity; • aktivnost sa transferazom;
Ćelijska komponenta	• citoplazma; • jedro; • nuclear envelope; • Fanconi anaemia nuclear complex; • nukleoplazma; • nuclear body; • intracellular membrane-bounded organelle;
Biološki proces	• protein ubiquitination; • gamete generation; • regulation of cell population proliferation; • interstrand cross-link repair; • protein monoubiquitination; • cellular response to DNA damage stimulus; • GO:0100026 Popravka DNK;
	Izvori:Amigo / QuickGO
Ortolozi
	55120
	67030
	ENSG00000115392
	ENSMUSG00000004018
	Q9NW38
	Q9CR14
	NM_001114636; NM_018062; NM_001374615
	NM_001277273; NM_025923
	NP_001108108; NP_060532; NP_001361544
	NP_001264202; NP_080199
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

E3 ubikvitin-protein ligaza FANCL jest enzim koji je kod ljudi kodiran genom FANCL sa p kraka hromosoma 2.^[5]

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 375 aminokiselina, a molekulska težina 42.905 Da.^[5]

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
MAVTEASLLR	QCPLLLPQNR	SKTVYEGFIS	AQGRDFHLRI	VLPEDLQLKN
ARLLCSWQLR	TILSGYHRIV	QQRMQHSPDL	MSFMMELKML	LEVALKNRQE
LYALPPPPQF	YSSLIEEIGT	LGWDKLVYAD	TCFSTIKLKA	EDASGREHLI
TLKLKAKYPA	ESPDYFVDFP	VPFCASWTPQ	SSLISIYSQF	LAAIESLKAF
WDVMDEIDEK	TWVLEPEKPP	RSATARRIAL	GNNVSINIEV	DPRHPTMLPE
CFFLGADHVV	KPLGIKLSRN	IHLWDPENSV	LQNLKDVLEI	DFPARAILEK
SDFTMDCGIC	YAYQLDGTIP	DQVCDNSQCG	QPFHQICLYE	WLRGLLTSRQ
SFNIIFGECP	YCSKPITLKM	SGRKH

Funkcija

**Rekombinacijski popravak oštećenja dvostrukog lanca DNK - neki ključni koraci.** ATM (ATM) je protein-kinaza koju regrutuju i aktiviraju dvolančani prekidi DNK. Dvolančana oštećenja DNK također aktiviraju jezgarni kompleks Fanconijeve anemije (FANCA/B/C/E/F/G/L/M).^[6] Jezgarni kompleks FA monoubikvitinira i nizvodno cilja na FANCD2 i FANCI.^[7] ATM aktivira fosforilira) CHEK2 i FANCD2^[8] CHEK2 fosforilira BRCA1.^[9] Ubikinirani kompleksi FANCD2 djeluju sa BRCA1 i RAD51.^[10] Protein PALB2 djeluje kao čvorište,^[11] spajajući BRCA1, BRCA2 i RAD51 na mjestu prekida dvolančane DNK, a također se vezuje za RAD51C, člana RAD51 paralognog kompleksa RAD51B-RAD51C-RAD51D-XRCC2 (BCDX2). Kompleks BCDX2 odgovoran je za angažovanje RAD51 ili stabilizaciju na mjestima oštećenja.^[12] RAD51 ima glavnu ulogu u homolognoj rekombinacijialnoj popravci DNK tokom popravljanja dvostrukog lanca. U ovom procesu, odvija se razmjena lanaca DNK, zavisna od ATP-a u kojoj jedan lanac napada lančiće uparene bazama homolognih molekula DNK. RAD51 je uključen u potragu za homologijom i fazama uparivanja lanaca u procesu.

Klinički fenotip mutacijskih defekata u svim komplementarnim grupama Fanconijeve anemije (FA) je sličan. Ovaj fenotip karakterizira progresivno zatajenje koštane srži, sklonost kanceru i tipski urođeni defekti.^[13] Glavni ćelijski fenotip je preosjetljivost na oštećenje DNK, posebno unakrsne veze DNK među lancima.^[14] FA proteini interaguju putem višeproteinskog puta. Međulančane umrežene veze DNK su veoma štetna oštećenja koja se popravljaju homolognom rekombinacijom, uključujući koordinaciju FA proteina i "gena za osjetljivost na rak dojke 1 (BRCA1)".

Put popravka DNK kod Fanconijeve anemije (FA) je neophodan za prepoznavanje i popravku umreženih međulančanih DNK (ICL). Kritični korak na putu je monoubikvitinacija FANCD2, pomoću RING E3-ligaza FANCL. FANCL se sastoji od tri domena, RING domena koji je u interakciji sa E2 konjugirajućim enzimima, centralnog domena potrebnog za interakciju supstrata i N-termin alnog E2-likog nabora domena (ELF) koji komunicira sa FANCB.^[15] ELF domen FANCL-a je također potreban da posreduje u nekovalentnoj interakciji između FANCL i ubikvitina. ELF domen je potrebna za podsgticanje efikasne monoubikvitinacije FANCD2 izazvane oštećenjem DNK u ćelijama kičmenjaka, što ukazuje na važnu funkciju FANCB i vezivanje ubikvitina od strane FANCL in vivo.^[16]

Jedarni kompleks koji sadrži FANCL (kao i FANCA, FANCB, FANCC, FANCE, FANCF, FANCG i FANCM) je neophodna za aktivaciju FANCD2 proteina na monoubikvitiniranu izoformu.^[6] U normalnim, nemutantnim, ćelijama FANCD2 je monoubikviniran kao odgovor na oštećenje DNK. Aktivirani protein FANCD2 kolokalizira se s BRCA1 (protein osjetljivosti na rak dojke) u žarištima izazvanim onizirajućim zračenjem i u sinaptonemskom kompleksu mejotskih hromosoma.

Reference

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000115392 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000004018 - Ensembl, maj 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ ^a ^b "Entrez Gene: FANCL Fanconi anemia, complementation group L".
^ ^a ^b D'Andrea AD (2010). "Susceptibility pathways in Fanconi's anemia and breast cancer". N. Engl. J. Med. 362 (20): 1909–19. doi:10.1056/NEJMra0809889. PMC 3069698. PMID 20484397.
^ Sobeck A, Stone S, Landais I, de Graaf B, Hoatlin ME (2009). "The Fanconi anemia protein FANCM is controlled by FANCD2 and the ATR/ATM pathways". J. Biol. Chem. 284 (38): 25560–8. doi:10.1074/jbc.M109.007690. PMC 2757957. PMID 19633289.
^ Castillo P, Bogliolo M, Surralles J (2011). "Coordinated action of the Fanconi anemia and ataxia telangiectasia pathways in response to oxidative damage". DNA Repair (Amst.). 10 (5): 518–25. doi:10.1016/j.dnarep.2011.02.007. PMID 21466974.
^ Stolz A, Ertych N, Bastians H (2011). "Tumor suppressor CHK2: regulator of DNA damage response and mediator of chromosomal stability". Clin. Cancer Res. 17 (3): 401–5. doi:10.1158/1078-0432.CCR-10-1215. PMID 21088254.
^ Taniguchi T, Garcia-Higuera I, Andreassen PR, Gregory RC, Grompe M, D'Andrea AD (2002). "S-phase-specific interaction of the Fanconi anemia protein, FANCD2, with BRCA1 and RAD51". Blood. 100 (7): 2414–20. doi:10.1182/blood-2002-01-0278. PMID 12239151.
^ Park JY, Zhang F, Andreassen PR (2014). "PALB2: the hub of a network of tumor suppressors involved in DNA damage responses". Biochim. Biophys. Acta. 1846 (1): 263–75. doi:10.1016/j.bbcan.2014.06.003. PMC 4183126. PMID 24998779.
^ Chun J, Buechelmaier ES, Powell SN (2013). "Rad51 paralog complexes BCDX2 and CX3 act at different stages in the BRCA1-BRCA2-dependent homologous recombination pathway". Mol. Cell. Biol. 33 (2): 387–95. doi:10.1128/MCB.00465-12. PMC 3554112. PMID 23149936.
^ Walden, Helen; Deans, Andrew J. (2014). "The Fanconi anemia DNA repair pathway: structural and functional insights into a complex disorder". Annual Review of Biophysics. 43: 257–278. doi:10.1146/annurev-biophys-051013-022737. ISSN 1936-1238. PMID 24773018.
^ Deans, Andrew J.; West, Stephen C. (24. 6. 2011). "DNA interstrand crosslink repair and cancer". Nature Reviews. Cancer. 11 (7): 467–480. doi:10.1038/nrc3088. ISSN 1474-1768. PMC 3560328. PMID 21701511.
^ van Twest, Sylvie; Murphy, Vincent J.; Hodson, Charlotte; Tan, Winnie; Swuec, Paolo; O'Rourke, Julienne J.; Heierhorst, Jörg; Crismani, Wayne; Deans, Andrew J. (19. 1. 2017). "Mechanism of Ubiquitination and Deubiquitination in the Fanconi Anemia Pathway". Molecular Cell. 65 (2): 247–259. doi:10.1016/j.molcel.2016.11.005. ISSN 1097-4164. PMID 27986371.
^ Miles JA, Frost MG, Carroll E, Rowe ML, Howard MJ, Sidhu A, Chaugule VK, Alpi AF, Walden H (2015). "The Fanconi Anemia DNA Repair Pathway Is Regulated by an Interaction between Ubiquitin and the E2-like Fold Domain of FANCL". J. Biol. Chem. 290 (34): 20995–1006. doi:10.1074/jbc.M115.675835. PMC 4543658. PMID 26149689.

Dopunska literatura

Maruyama K, Sugano S (1994). "Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides". Gene. 138 (1–2): 171–4. doi:10.1016/0378-1119(94)90802-8. PMID 8125298.
Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, et al. (1997). "Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library". Gene. 200 (1–2): 149–56. doi:10.1016/S0378-1119(97)00411-3. PMID 9373149.
Agoulnik AI, Lu B, Zhu Q, et al. (2003). "A novel gene, Pog, is necessary for primordial germ cell proliferation in the mouse and underlies the germ cell deficient mutation, gcd". Hum. Mol. Genet. 11 (24): 3047–53. doi:10.1093/hmg/11.24.3047. PMID 12417526.
Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. Bibcode:2002PNAS...9916899M. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
Lu B, Bishop CE (2003). "Mouse GGN1 and GGN3, two germ cell-specific proteins from the single gene Ggn, interact with mouse POG and play a role in spermatogenesis". J. Biol. Chem. 278 (18): 16289–96. doi:10.1074/jbc.M211023200. PMID 12574169.
Lu B, Bishop CE (2004). "Late onset of spermatogenesis and gain of fertility in POG-deficient mice indicate that POG is not necessary for the proliferation of spermatogonia". Biol. Reprod. 69 (1): 161–8. doi:10.1095/biolreprod.102.014654. PMID 12606378.
Meetei AR, Sechi S, Wallisch M, et al. (2003). "A Multiprotein Nuclear Complex Connects Fanconi Anemia and Bloom Syndrome". Mol. Cell. Biol. 23 (10): 3417–26. doi:10.1128/MCB.23.10.3417-3426.2003. PMC 164758. PMID 12724401.
Meetei AR, de Winter JP, Medhurst AL, et al. (2003). "A novel ubiquitin ligase is deficient in Fanconi anemia". Nat. Genet. 35 (2): 165–70. doi:10.1038/ng1241. PMID 12973351. S2CID 10149290.
Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The Status, Quality, and Expansion of the NIH Full-Length cDNA Project: The Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
Meetei AR, Levitus M, Xue Y, et al. (2004). "X-linked inheritance of Fanconi anemia complementation group B". Nat. Genet. 36 (11): 1219–24. doi:10.1038/ng1458. PMID 15502827.
Hillier LW, Graves TA, Fulton RS, et al. (2005). "Generation and annotation of the DNA sequences of human chromosomes 2 and 4". Nature. 434 (7034): 724–31. Bibcode:2005Natur.434..724H. doi:10.1038/nature03466. PMID 15815621.
Meetei AR, Medhurst AL, Ling C, et al. (2005). "A Human Orthologue of Archaeal DNA Repair Protein Hef is Defective in Fanconi Anemia Complementation Group M". Nat. Genet. 37 (9): 958–63. doi:10.1038/ng1626. PMC 2704909. PMID 16116422.
Gurtan AM, Stuckert P, D'Andrea AD (2006). "The WD40 repeats of FANCL are required for Fanconi anemia core complex assembly". J. Biol. Chem. 281 (16): 10896–905. doi:10.1074/jbc.M511411200. PMID 16474167.
Zhang J, Wang X, Lin CJ, et al. (2007). "Altered expression of FANCL confers mitomycin C sensitivity in Calu-6 lung cancer cells". Cancer Biol. Ther. 5 (12): 1632–6. doi:10.4161/cbt.5.12.3351. PMID 17106252.

Vanjski linkovi

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000115392 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000004018 - 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.

[entrez-5] "Entrez Gene: FANCL Fanconi anemia, complementation group L".

[Andrea-6] D'Andrea AD (2010). "Susceptibility pathways in Fanconi's anemia and breast cancer". N. Engl. J. Med. 362 (20): 1909–19. doi:10.1056/NEJMra0809889. PMC 3069698. PMID 20484397.

[pmid19633289-7] Sobeck A, Stone S, Landais I, de Graaf B, Hoatlin ME (2009). "The Fanconi anemia protein FANCM is controlled by FANCD2 and the ATR/ATM pathways". J. Biol. Chem. 284 (38): 25560–8. doi:10.1074/jbc.M109.007690. PMC 2757957. PMID 19633289.

[Castillo-8] Castillo P, Bogliolo M, Surralles J (2011). "Coordinated action of the Fanconi anemia and ataxia telangiectasia pathways in response to oxidative damage". DNA Repair (Amst.). 10 (5): 518–25. doi:10.1016/j.dnarep.2011.02.007. PMID 21466974.

[pmid21088254-9] Stolz A, Ertych N, Bastians H (2011). "Tumor suppressor CHK2: regulator of DNA damage response and mediator of chromosomal stability". Clin. Cancer Res. 17 (3): 401–5. doi:10.1158/1078-0432.CCR-10-1215. PMID 21088254.

[pmid12239151-10] Taniguchi T, Garcia-Higuera I, Andreassen PR, Gregory RC, Grompe M, D'Andrea AD (2002). "S-phase-specific interaction of the Fanconi anemia protein, FANCD2, with BRCA1 and RAD51". Blood. 100 (7): 2414–20. doi:10.1182/blood-2002-01-0278. PMID 12239151.

[pmid24998779-11] Park JY, Zhang F, Andreassen PR (2014). "PALB2: the hub of a network of tumor suppressors involved in DNA damage responses". Biochim. Biophys. Acta. 1846 (1): 263–75. doi:10.1016/j.bbcan.2014.06.003. PMC 4183126. PMID 24998779.

[Chun-12] Chun J, Buechelmaier ES, Powell SN (2013). "Rad51 paralog complexes BCDX2 and CX3 act at different stages in the BRCA1-BRCA2-dependent homologous recombination pathway". Mol. Cell. Biol. 33 (2): 387–95. doi:10.1128/MCB.00465-12. PMC 3554112. PMID 23149936.

[13] Walden, Helen; Deans, Andrew J. (2014). "The Fanconi anemia DNA repair pathway: structural and functional insights into a complex disorder". Annual Review of Biophysics. 43: 257–278. doi:10.1146/annurev-biophys-051013-022737. ISSN 1936-1238. PMID 24773018.

[14] Deans, Andrew J.; West, Stephen C. (24. 6. 2011). "DNA interstrand crosslink repair and cancer". Nature Reviews. Cancer. 11 (7): 467–480. doi:10.1038/nrc3088. ISSN 1474-1768. PMC 3560328. PMID 21701511.

[15] van Twest, Sylvie; Murphy, Vincent J.; Hodson, Charlotte; Tan, Winnie; Swuec, Paolo; O'Rourke, Julienne J.; Heierhorst, Jörg; Crismani, Wayne; Deans, Andrew J. (19. 1. 2017). "Mechanism of Ubiquitination and Deubiquitination in the Fanconi Anemia Pathway". Molecular Cell. 65 (2): 247–259. doi:10.1016/j.molcel.2016.11.005. ISSN 1097-4164. PMID 27986371.

[pmid26149689-16] Miles JA, Frost MG, Carroll E, Rowe ML, Howard MJ, Sidhu A, Chaugule VK, Alpi AF, Walden H (2015). "The Fanconi Anemia DNA Repair Pathway Is Regulated by an Interaction between Ubiquitin and the E2-like Fold Domain of FANCL". J. Biol. Chem. 290 (34): 20995–1006. doi:10.1074/jbc.M115.675835. PMC 4543658. PMID 26149689.

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p r u Enzimi
Teme	Aktivno mjesto Alosterna regulacija Difuzijski limitirani enzim EC broj Enzimska kataliza Inhibicija enzimskih reakcija Kinetika enzima Koenzim Kooperativnost Lineweaver–Burkov dijagram Michaelis–Mentenova kinetika Mjesto vezanja Spisak enzima
Tipovi	EC1 Oksidoreduktaze/spisak EC2 Transferaze/spisak EC3 Hidrolaze/spisak EC4 Lijaze/spisak EC5 Izomeraze/spisak EC6 Ligaze/spisak