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FANCD2 (Fanconi anemia, complementation group D2)

Identity

Other namesFAD
FAD2
FACD
FANCD
HGNC (Hugo) FANCD2
Location 3p25-26
Location_base_pair Starts at 10043113 and ends at 10118614 bp from pter ( according to hg18-Mar_2006)  [Mapping]
Local_order not far from XPC, in 3p25

DNA/RNA

Description 44 exons; 4356 bp open reading frame; the first exon is non-coding.

Protein

Description 1452 amino acids; 155 kDa (FANCD2-S isoform, for short), and 162 kDa (FANCD2-L isoform, for long) by ubiquitin addition
Expression weak
Localisation nucleus
Function the FA complex is comprised of : FANCA, FANCC, FANCE, FANCF, and FANCG; this complex is only found in the nucleus.
  • FANCA and FANCG form a complex in the cytoplasm, through a N-term FANCA (involving the nuclear localization signal) - FANCG interaction; FANCC join the complex; phosphorylation of FANCA would induce its translocation into the nucleus.This FA complex translocates into the nucleus, where FANCE and FANCF are present; FANCE and FANCF join the complex. The FA complex subsequently interacts with FANCD2 by monoubiquitination of FANCD2 during S phase or following DNA damage. Activated (ubiquinated ) FANCD2 (i.e. FANCD2-L), downstream in the FA pathway, will then interact with other proteins involved in DNA repair, possibly BRCA1; after DNA repair, FANCD2 return to the non-ubiquinated form (FANCD2-S).
  • FANCD2co-localizes with BRCA1 in DNA damaged-induced loci and in the synaptonemal complex of meotic chromosomes as well.
    • Homology significant homologies can be found with proteins from various species

    Implicated in

    Entity Fanconi anaemia (FA); FANCD2 is implicated in the FA complementation group D, a heterogeneous group, with at least 2 genes: FANCD2, and a yet undiscovered FANCD1. FA complementation group D represents about 1% of FA cases. In FA complementation group D patients, the FA complex is normal, in contrast with results found in group A, B (with a yet unknown gene), C, E, F, and G patients.
    Disease Fanconi anaemia is a chromosome instability syndrome/cancer prone disease (at risk of leukaemia and squamous cell carcinoma)
    Prognosis Fanconi anaemia's prognosis is poor; mean survival is 20 years: patients die of bone marrow failure (infections, haemorrhages), leukaemia, or solid cancer.
  • It has recently been shown that significant phenotypic differences were found between the various complementation groups. Patients from the rare groups FA-D, FA-E, and FA-F had somatic abnormalities more frequently.
    • Cytogenetics Spontaneously enhanced chromatid-type aberrations (breaks, gaps, interchanges; increased rate of breaks compared to control, when induced by specific clastogens known as DNA cross-linking agents (e.g. mitomycin C, diepoxybutane).
      

    External links

    Nomenclature
    HGNC (Hugo)FANCD2   3585
    Entrez_Gene (NCBI)FANCD2  2177  Fanconi anemia, complementation group D2
    Cards
    AtlasFAD
    GeneCards (Weizmann)FANCD2
    Ensembl (Hinxton)ENSG00000144554 [Gene_View]  FANCD2 [Vega]
    AceView (NCBI)FANCD2
    Genatlas (Paris)FANCD2
    euGene (Indiana)2177
    SOURCE (Stanford)NM_001018115 NM_033084
    Genomic and cartography
    GoldenPath (UCSC)FANCD2  -     chr3:10043113-10118614 +  3p25.3   [Description]    (hg18-Mar_2006)
    EnsemblFANCD2 - 3p25.3 [CytoView]
    Mapping of homologs : NCBIFANCD2 [Mapview]
    OMIM227646   
    Gene and transcription
    Gene : Genbank (Entrez)AF230336 AF340183 AK022613 AK074406 AK307512
    Reference sequence (RefSeq transcript) :SRSNM_001018115 NM_033084
    Reference transcript : EntrezNM_001018115 NM_033084
    RefSeq genomic : SRSAC_000046 AC_000135 NC_000003 NG_007311 NT_022517 NW_001838876 NW_921651
    RefSeq genomic : EntrezAC_000046 AC_000135 NC_000003 NG_007311 NT_022517 NW_001838876 NW_921651
    Consensus coding sequences : CCDS NCBIFANCD2
    Cluster EST : UnigeneHs.208388 [ SRS ] Hs.208388 [ NCBI ]
    Alternative Splicing : Fast-db (Paris)1833
    Protein : pattern, domain, 3D structure
    Protein : UniProt/SwissProtQ9BXW9 (SRS) Q9BXW9 (Expasy) Q9BXW9 (Uniprot)
    With graphics : InterProQ9BXW9
    Splice isoforms : VarSplice FASTAQ9BXW9(VarSplice FASTA)
    Related proteins : CluSTrQ9BXW9
    Domain families : Pfam SRS
    Domain families : Pfam Sanger
    Domain families : Pfam NCBI
    Blocks (Seattle)Q9BXW9
    Crystal structure of protein : PDB SRS
    Crystal structure of protein : PDBSum
    Crystal structure of protein : IMB
    Crystal structure of protein : PDB RSDB
    HPRD01968
    Protein Interaction databases
    DIP (DOE-UCLA)Q9BXW9
    IntAct (EBI)Q9BXW9
    Polymorphism : SNP, mutations, diseases
    Single Nucleotide Polymorphism (SNP) : dbSNP NCBIFANCD2
    SNP : GeneSNP UtahFANCD2
    SNP : HGBaseFANCD2
    Genetic variants : HAPMAPFANCD2
    Somatic Mutations in Cancer : COSMICFANCD2 
    Mutations and Diseases : HGMDFANCD2
    Hereditary diseases : OMIM227646   
    Hereditary diseases : GENETests227646   
    Diseases : Genetic AssociationFANCD2
    General knowledge
    Homologs : HomoloGeneFANCD2
    Homology/Alignments : Family Browser UCSCFANCD2
    Phylogenetic Trees/Animal Genes : TreeFamFANCD2
    Chemical/Protein Interactions : CTD2177
    Keywords Ontology : AmiGOmolecular_function  protein binding  cellular_component  nucleus  chromosome  DNA repair  response to DNA damage stimulus  cell cycle  biological_process  response to gamma radiation  
    Keywords Ontology : EGO-EBImolecular_function  protein binding  cellular_component  nucleus  chromosome  DNA repair  response to DNA damage stimulus  cell cycle  biological_process  response to gamma radiation  
    Pathways : BIOCARTARole of BRCA1, BRCA2 and ATR in Cancer Susceptibility [Genes]    BRCA1-dependent Ub-ligase activity [Genes]   
    Pathways : KEGG
    Other databases
    Other databaseFanconi anemia mutation database
    Probes
    ProbeCancer Cytogenetics (Bari)
    Probes : ImagenesFANCD2 Related clones (RZPD - Berlin)
    Literature
    PubMed61 Pubmed reference(s) in Entrez
    PubGeneFANCD2

    Bibliography

    Microcell mediated chromosome transfer maps the Fanconi anaemia group D gene to chromosome 3p.
    Whitney M, Thayer M, Reifsteck C, Olson S, Smith L, Jakobs PM, Leach R, Naylor S, Joenje H, Grompe M
    Nature genetics. 1995 ; 11 (3) : 341-343.
    PMID 7581463
     
    Molecular biology of Fanconi anemia: implications for diagnosis and therapy.
    D'Andrea AD, Grompe M
    Blood. 1997 ; 90 (5) : 1725-1736.
    PMID 9292505
     
    Fanconi anemia proteins FANCA, FANCC, and FANCG/XRCC9 interact in a functional nuclear complex.
    Garcia-Higuera I, Kuang Y, Nˆ§f D, Wasik J, D'Andrea AD
    Molecular and cellular biology. 1999 ; 19 (7) : 4866-4873.
    PMID 10373536
     
    Association of complementation group and mutation type with clinical outcome in fanconi anemia. European Fanconi Anemia Research Group.
    Faivre L, Guardiola P, Lewis C, Dokal I, Ebell W, Zatterale A, Altay C, Poole J, Stones D, Kwee ML, van Weel-Sipman M, Havenga C, Morgan N, de Winter J, Digweed M, Savoia A, Pronk J, de Ravel T, Jansen S, Joenje H, Gluckman E, Mathew CG
    Blood. 2000 ; 96 (13) : 4064-4070.
    PMID 11110674
     
    Localization of the Fanconi anemia complementation group D gene to a 200-kb region on chromosome 3p25.3.
    Hejna JA, Timmers CD, Reifsteck C, Bruun DA, Lucas LW, Jakobs PM, Toth-Fejel S, Unsworth N, Clemens SL, Garcia DK, Naylor SL, Thayer MJ, Olson SB, Grompe M, Moses RE
    American journal of human genetics. 2000 ; 66 (5) : 1540-1551.
    PMID 10762542
     
    Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway.
    Garcia-Higuera I, Taniguchi T, Ganesan S, Meyn MS, Timmers C, Hejna J, Grompe M, D'Andrea AD
    Molecular cell. 2001 ; 7 (2) : 249-262.
    PMID 11239454
     
    Fanconi anemia and DNA repair.
    Grompe M, D'Andrea A
    Human molecular genetics. 2001 ; 10 (20) : 2253-2259.
    PMID 11673408
     
    Direct interactions of the five known Fanconi anaemia proteins suggest a common functional pathway.
    Medhurst AL, Huber PA, Waisfisz Q, de Winter JP, Mathew CG
    Human molecular genetics. 2001 ; 10 (4) : 423-429.
    PMID 11157805
     
    Fanconi anemia proteins localize to chromatin and the nuclear matrix in a DNA damage- and cell cycle-regulated manner.
    Qiao F, Moss A, Kupfer GM
    The Journal of biological chemistry. 2001 ; 276 (26) : 23391-23396.
    PMID 11297559
     
    Targeted disruption of the murine Fanconi anemia gene, Fancg/Xrcc9.
    Yang Y, Kuang Y, Montes De Oca R, Hays T, Moreau L, Lu N, Seed B, D'Andrea AD
    Blood. 2001 ; 98 (12) : 3435-3440.
    PMID 11719385
     
    Positional cloning of a novel Fanconi anemia gene, FANCD2.
    Timmers C, Taniguchi T, Hejna J, Reifsteck C, Lucas L, Bruun D, Thayer M, Cox B, Olson S, D'Andrea AD, Moses R, Grompe M
    Molecular cell. 2001 ; 7 (2) : 241-248.
    PMID 11239453
     
    The Chinese hamster FANCG/XRCC9 mutant NM3 fails to express the monoubiquitinated form of the FANCD2 protein, is hypersensitive to a range of DNA damaging agents and exhibits a normal level of spontaneous sister chromatid exchange.
    Wilson JB, Johnson MA, Stuckert AP, Trueman KL, May S, Bryant PE, Meyn RE, D'Andrea AD, Jones NJ
    Carcinogenesis. 2001 ; 22 (12) : 1939-1946.
    PMID 11751423
     
    Current knowledge on the pathophysiology of Fanconi anemia: from genes to phenotypes.
    Yamashita T, Nakahata T
    International journal of hematology. 2001 ; 74 (1) : 33-41.
    PMID 11530803
     
    Breaks at telomeres and TRF2-independent end fusions in Fanconi anemia.
    Callˆ©n E, Samper E, Ramˆ‚rez MJ, Creus A, Marcos R, Ortega JJ, Olivˆ© T, Badell I, Blasco MA, Surrallˆ©s J
    Human molecular genetics. 2002 ; 11 (4) : 439-444.
    PMID 11854176
     
    REVIEW articlesautomatic search in PubMed
    Last year publicationsautomatic search in PubMed

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    Contributor(s)

    Written04-1998Jean-Loup Huret
    Updated06-2002Jean-Loup Huret

    Citation

    This paper should be referenced as such :
    Huret JL . FANCD2 (Fanconi anemia, complementation group D2). Atlas Genet Cytogenet Oncol Haematol. April 1998 .
    URL : http://AtlasGeneticsOncology.org/Genes/FAD.html
    Huret JL . FANCD2 (Fanconi anemia, complementation group D2). Atlas Genet Cytogenet Oncol Haematol. June 2002 .
    URL : http://AtlasGeneticsOncology.org/Genes/FAD.html

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    indexed on : Sat Jun 27 16:37:26 CEST 2009
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