ID FANCL_HUMAN Reviewed; 375 AA.
AC Q9NW38; Q6GU60;
DT 10-OCT-2003, integrated into UniProtKB/Swiss-Prot.
DT 17-OCT-2006, sequence version 2.
DT 01-MAY-2013, entry version 112.
DE RecName: Full=E3 ubiquitin-protein ligase FANCL;
DE EC=6.3.2.-;
DE AltName: Full=Fanconi anemia group L protein;
DE AltName: Full=Fanconi anemia-associated polypeptide of 43 kDa;
DE Short=FAAP43;
GN Name=FANCL; Synonyms=PHF9;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Teratocarcinoma;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Brain, and Eye;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP IDENTIFICATION BY MASS SPECTROMETRY IN A BRAFT COMPLEX WITH FANCA;
RP FANCC; FANCE; FANCF AND FANCG.
RX PubMed=12724401; DOI=10.1128/MCB.23.10.3417-3426.2003;
RA Meetei A.R., Sechi S., Wallisch M., Yang D., Young M.K., Joenje H.,
RA Hoatlin M.E., Wang W.;
RT "A multiprotein nuclear complex connects Fanconi anemia and Bloom
RT syndrome.";
RL Mol. Cell. Biol. 23:3417-3426(2003).
RN [5]
RP FUNCTION, SUBCELLULAR LOCATION, INVOLVEMENT IN FANCL, INTERACTION WITH
RP FANCA; FANCC; FANCF AND FANCG, AND MUTAGENESIS OF CYS-307 AND CYS-310.
RX PubMed=12973351; DOI=10.1038/ng1241;
RA Meetei A.R., de Winter J.P., Medhurst A.L., Wallisch M., Waisfisz Q.,
RA van de Vrugt H.J., Oostra A.B., Yan Z., Ling C., Bishop C.E.,
RA Hoatlin M.E., Joenje H., Wang W.;
RT "A novel ubiquitin ligase is deficient in Fanconi anemia.";
RL Nat. Genet. 35:165-170(2003).
RN [6]
RP IDENTIFICATION IN A COMPLEX WITH FANCA; FANCB; FANCC; FANCE; FANCF AND
RP FANCLG.
RX PubMed=15502827; DOI=10.1038/ng1458;
RA Meetei A.R., Levitus M., Xue Y., Medhurst A.L., Zwaan M., Ling C.,
RA Rooimans M.A., Bier P., Hoatlin M., Pals G., de Winter J.P., Wang W.,
RA Joenje H.;
RT "X-linked inheritance of Fanconi anemia complementation group B.";
RL Nat. Genet. 36:1219-1224(2004).
RN [7]
RP IDENTIFICATION IN A COMPLEX WITH FANCA; FANCB; FANCC; FANCE; FANCF;
RP FANCG AND FANCM.
RX PubMed=16116422; DOI=10.1038/ng1626;
RA Meetei A.R., Medhurst A.L., Ling C., Xue Y., Singh T.R., Bier P.,
RA Steltenpool J., Stone S., Dokal I., Mathew C.G., Hoatlin M.,
RA Joenje H., de Winter J.P., Wang W.;
RT "A human ortholog of archaeal DNA repair protein Hef is defective in
RT Fanconi anemia complementation group M.";
RL Nat. Genet. 37:958-963(2005).
RN [8]
RP FUNCTION, INTERACTION WITH UBE2T, UBIQUITINATION, AND MUTAGENESIS OF
RP CYS-307 AND TRP-341.
RX PubMed=16916645; DOI=10.1016/j.molcel.2006.06.024;
RA Machida Y.J., Machida Y., Chen Y., Gurtan A.M., Kupfer G.M.,
RA D'Andrea A.D., Dutta A.;
RT "UBE2T is the E2 in the Fanconi anemia pathway and undergoes negative
RT autoregulation.";
RL Mol. Cell 23:589-596(2006).
RN [9]
RP FUNCTION, INTERACTION WITH UBE2T, AND MUTAGENESIS OF CYS-307 AND
RP CYS-310.
RX PubMed=17938197; DOI=10.1128/MCB.00504-07;
RA Alpi A., Langevin F., Mosedale G., Machida Y.J., Dutta A., Patel K.J.;
RT "UBE2T, the Fanconi anemia core complex, and FANCD2 are recruited
RT independently to chromatin: a basis for the regulation of FANCD2
RT monoubiquitination.";
RL Mol. Cell. Biol. 27:8421-8430(2007).
RN [10]
RP INTERACTION WITH HES1, AND SUBCELLULAR LOCATION.
RX PubMed=18550849; DOI=10.1182/blood-2008-04-152710;
RA Tremblay C.S., Huang F.F., Habi O., Huard C.C., Godin C., Levesque G.,
RA Carreau M.;
RT "HES1 is a novel interactor of the Fanconi anemia core complex.";
RL Blood 112:2062-2070(2008).
RN [11]
RP FUNCTION, INTERACTION WITH UBE2T AND UBE2W, AND MUTAGENESIS OF
RP 158-TYR-PRO-159; CYS-307 AND CYS-359.
RX PubMed=19111657; DOI=10.1016/j.molcel.2008.12.003;
RA Alpi A.F., Pace P.E., Babu M.M., Patel K.J.;
RT "Mechanistic insight into site-restricted monoubiquitination of FANCD2
RT by Ube2t, FANCL, and FANCI.";
RL Mol. Cell 32:767-777(2008).
RN [12]
RP FUNCTION, AND MUTAGENESIS OF CYS-307.
RX PubMed=19589784; DOI=10.1074/jbc.C109.038075;
RA Longerich S., San Filippo J., Liu D., Sung P.;
RT "FANCI binds branched DNA and is monoubiquitinated by UBE2T-FANCL.";
RL J. Biol. Chem. 284:23182-23186(2009).
RN [13]
RP IDENTIFICATION IN THE FA COMPLEX.
RX PubMed=22343915; DOI=10.1182/blood-2011-10-385963;
RA Ali A.M., Pradhan A., Singh T.R., Du C., Li J., Wahengbam K.,
RA Grassman E., Auerbach A.D., Pang Q., Meetei A.R.;
RT "FAAP20: a novel ubiquitin-binding FA nuclear core-complex protein
RT required for functional integrity of the FA-BRCA DNA repair pathway.";
RL Blood 119:3285-3294(2012).
RN [14]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 109-294, INTERACTION WITH
RP FANCI AND UBE2T, AND MUTAGENESIS OF 127-VAL-TYR-128; LEU-149; PHE-166;
RP 212-TRP--LEU-214; LEU-248; PHE-252; LEU-254 AND ILE-265.
RX PubMed=21775430; DOI=10.1074/jbc.M111.244632;
RA Hodson C., Cole A.R., Lewis L.P., Miles J.A., Purkiss A., Walden H.;
RT "Structural analysis of human FANCL, the E3 ligase in the Fanconi
RT anemia pathway.";
RL J. Biol. Chem. 286:32628-32637(2011).
CC -!- FUNCTION: Ubiquitin ligase protein that mediates
CC monoubiquitination of FANCD2, a key step in the DNA damage
CC pathway. Also mediates monoubiquitination of FANCI. May stimulate
CC the ubiquitin release from UBE2W. May be required for proper
CC primordial germ cell proliferation in the embryonic stage, whereas
CC it is probably not needed for spermatogonial proliferation after
CC birth.
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Interacts with GGN (By similarity). Belongs to the
CC multisubunit FA complex composed of FANCA, FANCB, FANCC, FANCE,
CC FANCF, FANCG, FANCL/PHF9 and FANCM. The complex is not found in FA
CC patients. In complex with FANCF, FANCA and FANCG, but not with
CC FANCC, nor FANCE, interacts with HES1; this interaction may be
CC essential for the stability and nuclear localization of FA core
CC complex proteins. Interacts with FANCI. Interacts (via the RING-
CC type zinc finger) with UBE2T and UBE2W.
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q9NW38-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9NW38-2; Sequence=VSP_041727;
CC -!- DOMAIN: The UBC-RWD region (URD) region mediates interaction with
CC FANCI and FANCD2 (PubMed:21775430).
CC -!- PTM: The RING-type zinc finger domain is monoubiquitinated in the
CC presence of UBE2T and UBE2W.
CC -!- DISEASE: Fanconi anemia complementation group L (FANCL)
CC [MIM:614083]: A disorder affecting all bone marrow elements and
CC resulting in anemia, leukopenia and thrombopenia. It is associated
CC with cardiac, renal and limb malformations, dermal pigmentary
CC changes, and a predisposition to the development of malignancies.
CC At the cellular level it is associated with hypersensitivity to
CC DNA-damaging agents, chromosomal instability (increased chromosome
CC breakage) and defective DNA repair. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Contains 1 RING-type zinc finger.
CC -!- CAUTION: Although PubMed:12724401 reports that it contains a PHD-
CC type zinc finger, it contains a RING-type zinc finger. Moreover,
CC PHD-type zinc fingers do not have any ubiquitin ligase activity.
CC -!- WEB RESOURCE: Name=Fanconi Anemia Mutation Database;
CC URL="http://www.rockefeller.edu/fanconi/mutate/jumpl.html";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/FANCL";
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DR EMBL; AK001197; BAA91548.1; -; mRNA.
DR EMBL; AC007250; AAY15020.1; -; Genomic_DNA.
DR EMBL; BC009042; AAH09042.1; -; mRNA.
DR EMBL; BC054517; AAH54517.1; -; mRNA.
DR EMBL; BC037570; -; NOT_ANNOTATED_CDS; mRNA.
DR IPI; IPI00018099; -.
DR IPI; IPI00885015; -.
DR RefSeq; NP_001108108.1; NM_001114636.1.
DR RefSeq; NP_060532.2; NM_018062.3.
DR UniGene; Hs.741421; -.
DR PDB; 3ZQS; X-ray; 2.00 A; A/B=109-294.
DR PDBsum; 3ZQS; -.
DR ProteinModelPortal; Q9NW38; -.
DR IntAct; Q9NW38; 1.
DR MINT; MINT-2819517; -.
DR STRING; 9606.ENSP00000385021; -.
DR PhosphoSite; Q9NW38; -.
DR DMDM; 116241360; -.
DR PaxDb; Q9NW38; -.
DR PRIDE; Q9NW38; -.
DR Ensembl; ENST00000233741; ENSP00000233741; ENSG00000115392.
DR Ensembl; ENST00000402135; ENSP00000385021; ENSG00000115392.
DR GeneID; 55120; -.
DR KEGG; hsa:55120; -.
DR UCSC; uc002rzw.4; human.
DR UCSC; uc002rzx.4; human.
DR CTD; 55120; -.
DR GeneCards; GC02M058298; -.
DR HGNC; HGNC:20748; FANCL.
DR HPA; CAB033842; -.
DR HPA; HPA036685; -.
DR HPA; HPA036686; -.
DR MIM; 608111; gene.
DR MIM; 614083; phenotype.
DR neXtProt; NX_Q9NW38; -.
DR Orphanet; 84; Fanconi anemia.
DR PharmGKB; PA134887656; -.
DR eggNOG; NOG311231; -.
DR HOGENOM; HOG000007643; -.
DR HOVERGEN; HBG045632; -.
DR KO; K10606; -.
DR OMA; CFVDFPV; -.
DR PhylomeDB; Q9NW38; -.
DR Pathway_Interaction_DB; bard1pathway; BARD1 signaling events.
DR Reactome; REACT_216; DNA Repair.
DR UniPathway; UPA00143; -.
DR ChiTaRS; Fancl; human.
DR GenomeRNAi; 55120; -.
DR NextBio; 58768; -.
DR ArrayExpress; Q9NW38; -.
DR Bgee; Q9NW38; -.
DR CleanEx; HS_FANCL; -.
DR Genevestigator; Q9NW38; -.
DR GermOnline; ENSG00000115392; Homo sapiens.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0043240; C:Fanconi anaemia nuclear complex; IDA:UniProtKB.
DR GO; GO:0005635; C:nuclear envelope; IEA:Compara.
DR GO; GO:0004842; F:ubiquitin-protein ligase activity; IDA:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0006281; P:DNA repair; IMP:UniProtKB.
DR GO; GO:0007276; P:gamete generation; IEA:Compara.
DR GO; GO:0006513; P:protein monoubiquitination; IDA:UniProtKB.
DR GO; GO:0042127; P:regulation of cell proliferation; IEA:Compara.
DR Gene3D; 3.30.40.10; -; 1.
DR InterPro; IPR026848; Fancl.
DR InterPro; IPR019162; FancL_WD-rpt_cont_dom.
DR InterPro; IPR001841; Znf_RING.
DR InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR PANTHER; PTHR13206:SF0; PTHR13206:SF0; 1.
DR Pfam; PF09765; WD-3; 1.
DR SMART; SM00184; RING; 1.
DR PROSITE; PS00518; ZF_RING_1; FALSE_NEG.
DR PROSITE; PS50089; ZF_RING_2; FALSE_NEG.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Complete proteome; Cytoplasm;
KW DNA damage; DNA repair; Fanconi anemia; Ligase; Metal-binding;
KW Nucleus; Polymorphism; Reference proteome; Ubl conjugation;
KW Ubl conjugation pathway; Zinc; Zinc-finger.
FT CHAIN 1 375 E3 ubiquitin-protein ligase FANCL.
FT /FTId=PRO_0000055908.
FT ZN_FING 307 365 RING-type.
FT REGION 104 294 UBC-RWD region (URD).
FT VAR_SEQ 178 178 T -> TPQVNS (in isoform 2).
FT /FTId=VSP_041727.
FT VARIANT 144 144 S -> F (in dbSNP:rs36059257).
FT /FTId=VAR_052082.
FT MUTAGEN 127 128 VY->AA: Does not affect interaction with
FT FANCI and FANCD2.
FT MUTAGEN 149 149 L->A: Does not affect interaction with
FT FANCI and FANCD2; when associatec witt A-
FT 166.
FT MUTAGEN 158 159 YP->AA: Abolishes UBE2T charging.
FT MUTAGEN 166 166 F->A: Does not affect interaction with
FT FANCI and FANCD2; when associatec witt A-
FT 149.
FT MUTAGEN 212 214 WVL->AVA: Impairs interaction with FANCI
FT and FANCD2.
FT MUTAGEN 248 248 L->A: Impairs interaction with FANCI and
FT FANCD2; when associatec witt A-252.
FT MUTAGEN 252 252 F->A: Impairs interaction with FANCI and
FT FANCD2; when associatec witt A-248.
FT MUTAGEN 254 254 L->A: Impairs interaction with FANCI and
FT FANCD2; when associatec witt A-265.
FT MUTAGEN 265 265 I->A: Impairs interaction with FANCI and
FT FANCD2; when associatec witt A-254.
FT MUTAGEN 307 307 C->A: Abolishes ubiquitin ligase
FT activity.
FT MUTAGEN 310 310 C->A: Abolishes ubiquitin ligase
FT activity.
FT MUTAGEN 341 341 W->G: Abolishes interaction with UBE2T
FT and ubiquitin ligase activity.
FT MUTAGEN 359 359 C->A: Abolishes ubiquitin ligase
FT activity.
FT CONFLICT 77 77 S -> P (in Ref. 1; BAA91548).
FT HELIX 114 121
FT HELIX 123 125
FT STRAND 126 129
FT STRAND 133 141
FT STRAND 147 153
FT TURN 156 160
FT STRAND 164 166
FT HELIX 183 196
FT HELIX 198 210
FT STRAND 213 218
FT STRAND 225 231
FT STRAND 234 239
FT STRAND 250 255
FT HELIX 257 270
FT HELIX 271 273
FT HELIX 280 288
SQ SEQUENCE 375 AA; 42905 MW; E217DF9D64587E5E CRC64;
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
//
