ID:FACD2_HUMAN DESCRIPTION: RecName: Full=Fanconi anemia group D2 protein; Short=Protein FACD2; FUNCTION: Required for maintenance of chromosomal stability. Promotes accurate and efficient pairing of homologs during meiosis. Involved in the repair of DNA double-strand breaks, both by homologous recombination and single-strand annealing. May participate in S phase and G2 phase checkpoint activation upon DNA damage. Plays a role in preventing breakage and loss of missegregating chromatin at the end of cell division, particularly after replication stress. Required for the targeting, or stabilization, of BLM to non-centromeric abnormal structures induced by replicative stress. Promotes BRCA2/FANCD1 loading onto damaged chromatin. May also be involved in B-cell immunoglobulin isotype switching. SUBUNIT: Interacts directly with FANCE and FANCI. Interacts with USP1 and MEN1. The ubiquitinated form specifically interacts with BRCA1 and BLM. Both the nonubiquitinated and the monoubiquitinated forms interact with BRCA2; this interaction is mediated by phosphorylated FANCG and the complex also includes XCCR3. The ubiquitinated form specifically interacts with MTMR15/FAN1 (via UBZ-type zinc finger), leading to recruit MTMR15/FAN1 to sites of DNA damage. Interacts with DCLRE1B/Apollo. INTERACTION: P51587:BRCA2; NbExp=16; IntAct=EBI-359343, EBI-79792; Q9HB96:FANCE; NbExp=4; IntAct=EBI-359343, EBI-396803; Q9NVI1:FANCI; NbExp=2; IntAct=EBI-359343, EBI-1013291; Q16658:FSCN1; NbExp=6; IntAct=EBI-359343, EBI-351076; O00255:MEN1; NbExp=4; IntAct=EBI-359343, EBI-592789; SUBCELLULAR LOCATION: Nucleus. Note=Concentrates in nuclear foci during S phase and upon genotoxic stress. At the onset of mitosis, excluded from chromosomes and diffuses into the cytoplasm, returning to the nucleus at the end of cell division. Observed in a few spots localized in pairs on the sister chromatids of mitotic chromosome arms and not centromeres, one on each chromatids. These foci coincide with common fragile sites and could be sites of replication fork stalling. The foci are frequently interlinked through BLM-associated ultra-fine DNA bridges. Following aphidicolin treatment, targets chromatid gaps and breaks. TISSUE SPECIFICITY: Highly expressed in germinal center cells of the spleen, tonsil, and reactive lymph nodes, and in the proliferating basal layer of squamous epithelium of tonsil, esophagus, oropharynx, larynx and cervix. Expressed in cytotrophoblastic cells of the placenta and exocrine cells of the pancreas (at protein level). Highly expressed in testis, where expression is restricted to maturing spermatocytes. DEVELOPMENTAL STAGE: Highly expressed in fetal oocytes, and in hematopoietic cells of the fetal liver and bone marrow (at protein level). DOMAIN: The C-terminal 24 residues of isoform 2 are required for its function. PTM: Monoubiquitinated on Lys-561 during S phase and upon genotoxic stress by FANCL in complex with E2 ligases UBE2T or UBE2W (isoform 1 and isoform 2). Deubiquitinated by USP1 as cells enter G2/M, or once DNA repair is completed. Monoubiquitination requires the joint intervention of the FANC core complex, including FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, and FANCM, and proteins involved in cell cycle checkpoints and DNA repair, including RPA1, ATR, CHEK1 and BRCA1, and is mediated by FANCL/PHF9. Ubiquitination is required for binding to chromatin, interaction with BRCA1, BRCA2 and MTMR15/FAN1, DNA repair, and normal cell cycle progression, but not for phosphorylation on Ser- 222 or interaction with MEN1. PTM: Phosphorylated in response to various genotoxic stresses by ATM and/or ATR. Upon ionizing radiation, phosphorylated by ATM on Ser-222 and Ser-1404. Phosphorylation on Ser-222 is required for S-phase checkpoint activation, but not for ubiquitination, foci formation, or DNA repair. In contrast, phosphorylation by ATR on other sites may be required for ubiquitination and foci formation. DISEASE: Defects in FANCD2 are a cause of Fanconi anemia complementation group D type 2 (FANCD2) [MIM:227646]. A disorder affecting all bone marrow elements and resulting in anemia, leukopenia and thrombopenia. It is associated with cardiac, renal and limb malformations, dermal pigmentary changes, and a predisposition to the development of malignancies. At the cellular level it is associated with hypersensitivity to DNA-damaging agents, chromosomal instability (increased chromosome breakage) and defective DNA repair. SEQUENCE CAUTION: Sequence=BAB14132.1; Type=Erroneous initiation; Note=Translation N-terminally extended; WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/FAD.html"; WEB RESOURCE: Name=Fanconi Anemia Mutation Database; URL="http://www.rockefeller.edu/fanconi/mutate/jumpd2.html"; WEB RESOURCE: Name=GeneReviews; URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/FANCD2"; WEB RESOURCE: Name=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/fancd2/";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
Protein Domain and Structure Information
Pfam Domains: PF14631 - Fanconi anaemia protein FancD2 nuclease
ModBase Predicted Comparative 3D Structure on Q9BXW9
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
AK307512 - Homo sapiens cDNA, FLJ97460. AF230336 - Homo sapiens Fanconi anemia complementation group D2 protein (FANCD2) mRNA, complete cds. AF340183 - Homo sapiens Fanconi anemia complementation group D2 protein (FANCD2) mRNA, complete cds, alternatively spliced. BC038666 - Homo sapiens cDNA clone IMAGE:5268117, containing frame-shift errors. BC156799 - Synthetic construct Homo sapiens clone IMAGE:100062545, MGC:190555 Fanconi anemia, complementation group D2 (FANCD2) mRNA, encodes complete protein. AK022613 - Homo sapiens cDNA FLJ12551 fis, clone NT2RM4000700. AL832427 - Homo sapiens mRNA; cDNA DKFZp762A223 (from clone DKFZp762A223). BC013582 - Homo sapiens Fanconi anemia, complementation group D2, mRNA (cDNA clone IMAGE:3876190), complete cds. KJ901423 - Synthetic construct Homo sapiens clone ccsbBroadEn_10817 FANCD2 gene, encodes complete protein. KR711469 - Synthetic construct Homo sapiens clone CCSBHm_00024292 FANCD2 (FANCD2) mRNA, encodes complete protein. KR711470 - Synthetic construct Homo sapiens clone CCSBHm_00024293 FANCD2 (FANCD2) mRNA, encodes complete protein. JD502867 - Sequence 483891 from Patent EP1572962. JD265652 - Sequence 246676 from Patent EP1572962. JD433810 - Sequence 414834 from Patent EP1572962. AK074406 - Homo sapiens cDNA FLJ23826 fis, clone HUV00813, highly similar to Homo sapiens Fanconi anemia complementation group D2 protein (FANCD2) mRNA. JD257491 - Sequence 238515 from Patent EP1572962. JD493423 - Sequence 474447 from Patent EP1572962. JD091547 - Sequence 72571 from Patent EP1572962.
Biochemical and Signaling Pathways
BioCarta from NCI Cancer Genome Anatomy Project h_bard1Pathway - BRCA1-dependent Ub-ligase activity h_atrbrcaPathway - Role of BRCA1, BRCA2 and ATR in Cancer Susceptibility
Reactome (by CSHL, EBI, and GO)
Protein Q9BXW9 (Reactome details) participates in the following event(s):
R-HSA-6785594 FANCD2 binds FANCI R-HSA-6785342 FANCD2:FANCI complex and UBE2T bind ICL-DNA associated with the FA core complex R-HSA-6786171 FANCD2 deubiquitination by USP1:WDR48 R-HSA-6788385 The complex of ATR and ATRIP is recruited to ICL-DNA R-HSA-6785361 Monoubiquitination of FANCD2:FANCI R-HSA-6788392 ATR phosphorylates RPA2, FANCI, FANCD2 and FANCM at ICL-DNA R-HSA-6785732 DNA nucleases bind monoubiquitinated ID2 complex R-HSA-6786155 POLN binds ICL-DNA R-HSA-6783310 Fanconi Anemia Pathway R-HSA-6796648 TP53 Regulates Transcription of DNA Repair Genes R-HSA-73894 DNA Repair R-HSA-3700989 Transcriptional Regulation by TP53 R-HSA-212436 Generic Transcription Pathway R-HSA-73857 RNA Polymerase II Transcription R-HSA-74160 Gene expression (Transcription)
US Server
Sequence and Links to Tools and Databases 
Common Gene Haplotype Alleles 
