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   25-JAN-2012, entry version 98.
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   MEDLINE=22610328; PubMed=12724401;
RX   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   MEDLINE=22879927; 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   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).
CC   -!- FUNCTION: Ubiquitin ligase protein that mediates ubiquitination of
CC       FANCD2, a key step in the DNA damage pathway. May stimulate the
CC       ubiquitin release from UBE2W (By similarity). May be required for
CC       proper primordial germ cell proliferation in the embryonic stage,
CC       whereas it is probably not needed for spermatogonial proliferation
CC       after 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 UBE2W via the RING-type zinc
CC       finger (By similarity).
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   -!- PTM: The RING-type zinc finger domain is monoubiquitinated in
CC       vitro in the presence of UBE2W.
CC   -!- DISEASE: Defects in FANCL are the cause of Fanconi anemia
CC       complementation group L (FANCL) [MIM:614083]. FANCL is a disorder
CC       affecting all bone marrow elements and resulting in anemia,
CC       leukopenia and thrombopenia. It is associated with cardiac, renal
CC       and limb malformations, dermal pigmentary changes, and a
CC       predisposition to the development of malignancies. At the cellular
CC       level it is associated with hypersensitivity to DNA-damaging
CC       agents, chromosomal instability (increased chromosome breakage)
CC       and defective DNA repair.
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.631890; -.
DR   PDB; 3ZQS; X-ray; 2.00 A; A/B=109-294.
DR   PDBsum; 3ZQS; -.
DR   ProteinModelPortal; Q9NW38; -.
DR   SMR; Q9NW38; 109-294, 302-369.
DR   IntAct; Q9NW38; 1.
DR   MINT; MINT-2819517; -.
DR   STRING; Q9NW38; -.
DR   DMDM; 116241360; -.
DR   PRIDE; Q9NW38; -.
DR   Ensembl; ENST00000233741; ENSP00000233741; ENSG00000115392.
DR   GeneID; 55120; -.
DR   KEGG; hsa:55120; -.
DR   UCSC; uc002rzw.2; human.
DR   CTD; 55120; -.
DR   GeneCards; GC02M058298; -.
DR   H-InvDB; HIX0002071; -.
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; prNOG04061; -.
DR   GeneTree; ENSGT00390000005537; -.
DR   HOVERGEN; HBG045632; -.
DR   PhylomeDB; Q9NW38; -.
DR   Pathway_Interaction_DB; bard1pathway; BARD1 signaling events.
DR   Reactome; REACT_216; DNA Repair.
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:0004842; F:ubiquitin-protein ligase activity; ISS:UniProtKB.
DR   GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR   GO; GO:0006281; P:DNA repair; TAS:Reactome.
DR   InterPro; IPR019162; FancL_WD-rpt_cont_dom.
DR   InterPro; IPR001841; Znf_RING.
DR   InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR   Gene3D; G3DSA:3.30.40.10; Znf_RING/FYVE/PHD; 1.
DR   KO; K10606; -.
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   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     307    307       C->A: Abolishes ubiquitin ligase
FT                                activity.
FT   MUTAGEN     310    310       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
//