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FANCL (FA complementation group L)

Written2019-06Sylvie van Twest, Andrew Deans
St Vincent's Institute of Medical Research, 9 Princes St, Fitzroy VIC 3065; svantwest@svi.edu.au adeans@svi.edu.au

Keywords FANCL, RING E3 ligase, Fanconi Anemia, ubiquitination, cancer pre-disposition

(Note : for Links provided by Atlas : click)

Identity

Alias_namesPHF9
PHD finger protein 9
Alias_symbol (synonym)FLJ10335
FAAP43
Pog
Other aliasFA Complementation Group L
Fanconi Anemia-Associated Polypeptide Of 43 KDa
RING-Type E3 Ubiquitin Transferase FANCL
Fanconi Anemia Complementation Group L
E3 Ubiquitin-Protein Ligase FANCL
Fanconi Anemia Group L Protein
POG
HGNC (Hugo) FANCL
LocusID (NCBI) 55120
Atlas_Id 40529
Location FANCL is located on 2p16.1 which is the short arm (p) of chromosome 2 at position 16.1 between base pairs 58,159,243 to 58,241,681.  [Link to chromosome band 2p16]
Location_base_pair Starts at 58159243 and ends at 58241380 bp from pter ( according to hg19-Feb_2009)  [Mapping FANCL.png]
 
  Figure 1: Genomic context of FANCL on chromosome 2 (Adapted from NCBI).
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)

DNA/RNA

Note FANCL has 2 described isoforms produced by alternative splicing. Isoform one (Q9NW38-1). Is known as the canonical isoform, while isoform 2 (Q9NW38-2) differs from the canonical sequence at 178-178: T--> TPQVNS.

Protein

 
  Figure 2: Exons in FANCL gene. Colour coded to indicate ELF, DRWD, and RING finger domains. Adapted from Chandrasekharappa et al. 2013.
Description The FANCL gene encodes FANCL protein comprised of 375 amino acids with a molecular mass of 42905 Da. FANCL is comprised of 3 domains, an N-terminal E2-like fold (ELF), a novel double-RWD (DRWD) and C-terminal RING domain (Hodson, Purkiss et al., 2014).
Expression From total RNA sequencing, FANCL was found to be expressed in adrenal gland (RPKM 2.1), prostate (RPKM 2.34), thymus (RPKM 2.1), and thyroid (RPKM 2.2) (Bioproject PRJNA280600 (PMID 25970244 ). In another RNA sequencing project on 27 different tissues from 95 human individuals, FANCL was highly expressed in adrenal gland (RPKM 16.8), endometrium (RPKM 10.6), lymph nodes (RPKM 8.5), ovary (RPKM 9.2), prostate (RPKM 8.5), and testis (RPKM 12) (Bioproject PRJEB4337, PMID 24309898).
 
  Figure 3: A) Schematic of D2 monoubiquitination by E3 RING ligase FANCL and E2 conjugating enzyme. B) Ribbon diagram of FANCL with ELF domain (brown), DRWD domain (green), and RING domain (green). C) Surface representation of protein binding domains on FANCL. The binding patch for ubiquitin (orange) is within the ELF domain, while the substrate binding domain (red) is in the DRWD domain, and the Ube2t binding domain (light purple) is in the RING domain. Figure from Specificity and disease in the ubiquitin system by Viduth K. Chaugule and Helen Walden in Biochemical Society Transactions Feb 2016, 44 (1) 212-227; DOI: 10.1042/BST20150209.
Function FANCL the catalytically active part of the 9 protein Fanconi anemia (FA) core complex comprised of FANCB, FAAP100, FANCA, FANCG, FAAP20, FANCC, FANCE and FANCF that forms in response to DNA damage incurred during DNA replication in S-phase, or to detection of interstand cross links (ICL) (Ceccaldi, Sarangi et al., 2016). FANCL is an E3 ubiquitin ligase that specifically monoubiquitinates FANCD2 (at lysine 561) and FANCI (at lysine 523) (ID2; Note the FANCD2-FANCI heterodimer "ID2" must not to be confused with the gene ID2) in the presence ofUBE2T (FANCT) to signal downstream DNA repair proteins. FANCL is comprised of 3 distinct functional domains: the RING domain interacts with the E2 conjugating enzyme UBE2T (FANCT), the central DRWD domain interacts with FANCD2, and the N-terminal E2-like fold domain (ELF) domain interacts with ubiquitin (Hodson et al., 2014, Miles, Frost et al., 2015). Within the core complex, FANCL interacts as a subcomplex with FANCB and FAAP100 (Huang, Leung et al., 2014, van Twest, Murphy et al., 2017); both proteins stabilize FANCL (Rajendra, Oestergaard et al., 2014), and enhance it's activity 5-fold in vitro assays (Ling, Ishiai et al., 2007).
Along with FANCA, FANCG, FANCF, FANCL was found to interact directly with hairy enhancer of split 1 ( HES1), which is a part of the NOTCH1 developmental pathway involved hematopoietic stem cell (HSC) self-renewal (Tremblay, Huang et al., 2008). Depletion of HES1 from cells resulted in FA-like phenotype with disrupted interaction between individual core complex proteins, increased cell sensitivity to DNA crosslinking agents, and reduced MMC-induced ID2 monoubiquitination (Tremblay et al., 2008). Finally HES1 did not interact FA-mutated core complex proteins. HSC defects and eventual bone marrow failure in FA patients may be linked to inability of HES1 to interact with a defective core complex (Tremblay et al., 2008, Tremblay, Huang et al., 2018).
 
  Figure 4: Schematic of Fanconi Anemia DNA damage response pathway. In response to interstrand cross links (ICL), or DNA damage from DNA replication, FANCM recruits the 9 protein core complex to DNA damage sites to monoubiquitinate FANC D2 and I. The core complex is comprised of 3 sub-complexes AG20 (FANC A, G, FAAP20), BL100 (FANC B, L, FAAP100), and CEF (FANC C,E,F). Dashed lines indicate groupings of sub-complexes, while triple lines indicate putative direct protein interactions. Within the core complex, FANCL has a RING E3 domain with ubiquitin ligase activity, but mutation in any one of the FA genes leads to defective DNA repair. Ubiquitinated ID2 is activated, and localized to chromatin in nuclear foci to interact with downstream DNA repair proteins (FANCD1, FANCD1, FANCN) to repair DNA via homologous recombination. Once DNA repair is completed, USP1 deubiquitinates ID2 so that DNA damage response can be reinitiated. Figure adapted from https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/fancb

Mutations

Germinal FANCL-associated Fanconi anemia is inherited in an autosomal recessive manner, and accounts for 0.2% of all FA cases (Wu, Liu et al., 2017). To date, there are only 9 documented cases of FANCL-associated FA (Ali, Kirby et al., 2009, Ameziane, Sie et al., 2012, Chandrasekharappa, Lach et al., 2013, Meetei, de Winter et al., 2003, Vetro, Iascone et al., 2015, Wu et al., 2017).
Of the 5 cases with phenotypic and genotypic data, four were severe, and one was mild. Two severe cases frame shift deletions in exon 4 and 6 that truncated FANC, resulted in postnatal mortality and presented with VACTERL association (vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal malformations, and limb defects) (Vetro et al., 2015). Another case with homozygous frameshift insertion of exon 9 had a severe phenotype with esophageal atresia (Ameziane et al., 2012). Finally, a novel homozygous mutation c.822_823insCTTTCAGG (p.Asp275LeufsX13) had a typical FA presentation with progression to bone marrow failture and death at age 9 from acute myelomonocytic leukemia (AML-M4) (Wu et al., 2017). The patient with mild FANCL-associated FA had bi-allelic mutation (Ali et al., 2009). One allele had an in-frame 3-bp deletion c.1007_1009delTAT (p.Ile336_Cys337delinsSer) in exon 12 within the PHD/RING-finger domain that resulted in loss of one amino acid, isoleucine-336, and conversion of cysteine-337 to serine null mutation (produces non-function protein). The other mutated allele had a 4-bp duplication (c.1095_1098dupAATT (p.Thr367AsnfsX13) that resulted in a frameshift just outside the RING-finger domain in exon 14. 4-bp duplication mutation is a hypomorphic mutation (produces partially functional protein) (Ali et al., 2009).
Sequencing screen of 27 FA cases with unidentified mutations uncovered 3 FANCL FA associated mutations: c.375-2033C>G (skips exons 4,6,7), c.375-2033 C>G (multiple splicing aberrations), c.1092G>A (skips exon 13), but didn't have corresponding phenotypic data (Chandrasekharappa et al., 2013). There is no phenotypic data for the first FANCL-associated FA patient that had exon 11 deletion and insertion of 177-nt sequence (Meetei et al., 2003) .

Implicated in

  
Entity Fanconi Anemia
Disease Biallelic mutations in FANCL, or any of the other 21 FA pathway proteins is implicated in Fanconi Anemia (FA), a rare genetic condition that results in progressive bone marrow failure (pancytopenia), congenital malformations in 75% of patients (short stature, urogenital defects, café au lait spots, skeletal malformations), and cancer pre-disposition (primarily acute myeloid leukaemia, and certain solid tumours) (Alter, 2014). Mutations that result in loss-of-function of both FANCL alleles may correlate with more severe phenotypes (Vetro et al., 2015). Hydrocephalus-VACTERL (vertebral, anal, cardiac, tracheo-esophageal fistula, renal, and limb anomalies) syndrome has been reported in two FANCL-linked FA patients that died shortly after birth (Vetro et al., 2015).
Prognosis: The prognosis for FA is poor as there is no cure, and the average lifespan is 20-30 years. If no congenital abnormalities are apparent at birth, patients are often diagnosed with FA when they present with aplastic anemia ages 8-10 (>700 fold risk) (Alter, 2014). Bone marrow transplants are often conducted to correct the haematological issues associated with FA, however due to faulty DNA repair FA patients retain high cancer risk particularly leukaemia, and head and neck squamous cell carcinomas (approximately 500 fold risk) (Shimamura & Alter, 2010).
Diagnosis: Diagnostics for FA is done with a chromosomal breakage test; when treated with interstand crosslinking agents such as mitomycin C (MMC) or diepoxybutane (DEB) FA cells exhibit high number chromosomal breakages, and abnormalities as compared to normal cells.
  

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Citation

This paper should be referenced as such :
van Twest S, Deans A
FANCL (FA complementation group L);
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/FANCLID40529ch2p16.html


Other Cancer prone implicated (Data extracted from papers in the Atlas) [ 2 ]
  Fanconi anemia Familial Myeloproliferative Disorders


External links

Nomenclature
HGNC (Hugo)FANCL   20748
LRG (Locus Reference Genomic)LRG_501
Cards
AtlasFANCL40529ch2p16
Entrez_Gene (NCBI)FANCL  55120  FA complementation group L
AliasesFAAP43; PHF9; POG
GeneCards (Weizmann)FANCL
Ensembl hg19 (Hinxton)ENSG00000115392 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000115392 [Gene_View]  ENSG00000115392 [Sequence]  chr2:58159243-58241380 [Contig_View]  FANCL [Vega]
ICGC DataPortalENSG00000115392
TCGA cBioPortalFANCL
AceView (NCBI)FANCL
Genatlas (Paris)FANCL
WikiGenes55120
SOURCE (Princeton)FANCL
Genetics Home Reference (NIH)FANCL
Genomic and cartography
GoldenPath hg38 (UCSC)FANCL  -     chr2:58159243-58241380 -  2p16.1   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)FANCL  -     2p16.1   [Description]    (hg19-Feb_2009)
GoldenPathFANCL - 2p16.1 [CytoView hg19]  FANCL - 2p16.1 [CytoView hg38]
ImmunoBaseENSG00000115392
Mapping of homologs : NCBIFANCL [Mapview hg19]  FANCL [Mapview hg38]
OMIM608111   614083   
Gene and transcription
Genbank (Entrez)AK001197 AK225147 AK297736 AK309671 AL036481
RefSeq transcript (Entrez)NM_001114636 NM_018062
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)FANCL
Cluster EST : UnigeneHs.631890 [ NCBI ]
CGAP (NCI)Hs.631890
Alternative Splicing GalleryENSG00000115392
Gene ExpressionFANCL [ NCBI-GEO ]   FANCL [ EBI - ARRAY_EXPRESS ]   FANCL [ SEEK ]   FANCL [ MEM ]
Gene Expression Viewer (FireBrowse)FANCL [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)55120
GTEX Portal (Tissue expression)FANCL
Human Protein AtlasENSG00000115392-FANCL [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9NW38   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ9NW38  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9NW38
Splice isoforms : SwissVarQ9NW38
PhosPhoSitePlusQ9NW38
Domains : Interpro (EBI)Fancl    FANCL_C    FancL_WD-rpt_cont_dom    UBQ-conjugating_enzyme/RWD    Znf_RING/FYVE/PHD   
Domain families : Pfam (Sanger)FANCL_C (PF11793)    WD-3 (PF09765)   
Domain families : Pfam (NCBI)pfam11793    pfam09765   
Conserved Domain (NCBI)FANCL
DMDM Disease mutations55120
Blocks (Seattle)FANCL
PDB (RSDB)3ZQS    4CCG   
PDB Europe3ZQS    4CCG   
PDB (PDBSum)3ZQS    4CCG   
PDB (IMB)3ZQS    4CCG   
Structural Biology KnowledgeBase3ZQS    4CCG   
SCOP (Structural Classification of Proteins)3ZQS    4CCG   
CATH (Classification of proteins structures)3ZQS    4CCG   
SuperfamilyQ9NW38
Human Protein Atlas [tissue]ENSG00000115392-FANCL [tissue]
Peptide AtlasQ9NW38
HPRD06997
IPIIPI00018099   IPI00885015   IPI00894167   IPI00894304   IPI00894380   IPI00894516   IPI00892593   IPI00892731   
Protein Interaction databases
DIP (DOE-UCLA)Q9NW38
IntAct (EBI)Q9NW38
FunCoupENSG00000115392
BioGRIDFANCL
STRING (EMBL)FANCL
ZODIACFANCL
Ontologies - Pathways
QuickGOQ9NW38
Ontology : AmiGOubiquitin-protein transferase activity  ubiquitin-protein transferase activity  protein binding  nuclear envelope  nucleoplasm  cytoplasm  DNA repair  protein monoubiquitination  cellular response to DNA damage stimulus  gamete generation  nuclear body  ubiquitin protein ligase binding  interstrand cross-link repair  regulation of cell proliferation  intracellular membrane-bounded organelle  Fanconi anaemia nuclear complex  metal ion binding  ubiquitin protein ligase activity  
Ontology : EGO-EBIubiquitin-protein transferase activity  ubiquitin-protein transferase activity  protein binding  nuclear envelope  nucleoplasm  cytoplasm  DNA repair  protein monoubiquitination  cellular response to DNA damage stimulus  gamete generation  nuclear body  ubiquitin protein ligase binding  interstrand cross-link repair  regulation of cell proliferation  intracellular membrane-bounded organelle  Fanconi anaemia nuclear complex  metal ion binding  ubiquitin protein ligase activity  
Pathways : KEGGFanconi anemia pathway    Ubiquitin mediated proteolysis   
REACTOMEQ9NW38 [protein]
REACTOME PathwaysR-HSA-6783310 [pathway]   
NDEx NetworkFANCL
Atlas of Cancer Signalling NetworkFANCL
Wikipedia pathwaysFANCL
Orthology - Evolution
OrthoDB55120
GeneTree (enSembl)ENSG00000115392
Phylogenetic Trees/Animal Genes : TreeFamFANCL
HOGENOMQ9NW38
Homologs : HomoloGeneFANCL
Homology/Alignments : Family Browser (UCSC)FANCL
Gene fusions - Rearrangements
Fusion : FusionGDB12926    12927    41663   
Fusion : Fusion_HubABCB7--FANCL    CACNA2D3--FANCL    CANX--FANCL    CLASP1--FANCL    DNAH6--FANCL    FANCL--APP    FANCL--ERBB4    FANCL--FANCL    FANCL--PCMT1    FANCL--PHF10    FANCL--PRR16    FANCL--SEC23B    FANCL--TAF15    FANCL--TSPAN12    FGFR1OP--FANCL   
KANSL3--FANCL    MREG--FANCL    PPP3R1--FANCL    PRKD3--FANCL    SETD2--FANCL    SMEK2--FANCL    SPTBN1--FANCL    VPS13A--FANCL    VRK2--FANCL   
Fusion : QuiverFANCL
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerFANCL [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)FANCL
dbVarFANCL
ClinVarFANCL
1000_GenomesFANCL 
Exome Variant ServerFANCL
ExAC (Exome Aggregation Consortium)ENSG00000115392
GNOMAD BrowserENSG00000115392
Varsome BrowserFANCL
Genetic variants : HAPMAP55120
Genomic Variants (DGV)FANCL [DGVbeta]
DECIPHERFANCL [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisFANCL 
Mutations
ICGC Data PortalFANCL 
TCGA Data PortalFANCL 
Broad Tumor PortalFANCL
OASIS PortalFANCL [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICFANCL  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DFANCL
Mutations and Diseases : HGMDFANCL
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
LOVD (Leiden Open Variation Database)**PUBLIC** CCHMC Molecular Genetics Laboratory Mutation Database
LOVD (Leiden Open Variation Database)Fanconi anemia database
BioMutasearch FANCL
DgiDB (Drug Gene Interaction Database)FANCL
DoCM (Curated mutations)FANCL (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)FANCL (select a term)
intoGenFANCL
NCG5 (London)FANCL
Cancer3DFANCL(select the gene name)
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM608111    614083   
Orphanet634   
DisGeNETFANCL
MedgenFANCL
Genetic Testing Registry FANCL
NextProtQ9NW38 [Medical]
TSGene55120
GENETestsFANCL
Target ValidationFANCL
Huge Navigator FANCL [HugePedia]
snp3D : Map Gene to Disease55120
BioCentury BCIQFANCL
ClinGenFANCL
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD55120
Chemical/Pharm GKB GenePA134887656
Clinical trialFANCL
Miscellaneous
canSAR (ICR)FANCL (select the gene name)
DataMed IndexFANCL
Probes
Litterature
PubMed73 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
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