FANCD2

Fanconi anemia group D2 protein ;
Protein FACD2 ;

developmental stage:Highly expressed in fetal oocytes , and in hematopoietic cells of the fetal liver and bone marrow (at protein level) . ,disease:Defects in FANCD2 are a cause of Fanconi anemia (FA) [MIM:227650]. FA is a genetically heterogeneous , autosomal recessive disorder characterized by progressive pancytopenia , a diverse assortment of congenital malformations , 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. ,domain:The C-terminal 24 residues of isoform 2 are required for its function. ,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. Promotes BRCA2/FANCD1 loading onto damaged chromatin. May also be involved in B-cell immunoglobulin isotype switching. ,PTM:Monoubiquitinated on Lys-561 during S phase and upon genotoxic stress (isoform 1 and isoform 2) . Deubiquitinated by USP1 as cells enter G2/M , or once DNA repair is completed. Monoubiquitination requires the FANCA-FANCB-FANCC-FANCE-FANCF-FANCG-FANCM complex , RPA1 and ATR , and is mediated by FANCL/PHF9. Ubiquitination is required for binding to chromatin , interaction with BRCA1 and BRCA2 , 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. ,subcellular location:Concentrates in nuclear foci during S phase and upon genotoxic stress. ,subunit:Interacts directly with FANCE and FANCI. Interacts with USP1 and MEN1. The ubiquitinated form specifically interacts with BRCA1 , BRCA2 and BLM. ,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. ,

M phase , DNA metabolic process , DNA repair , response to DNA damage stimulus , cell cycle , meiosis , meiosis I ,synapsis , gamete generation , response to radiation , response to abiotic stimulus , response to ionizing radiation ,response to gamma radiation , sexual reproduction , cell cycle process , cell cycle phase , multicellular organism reproduction , cellular response to stress , reproductive process in a multicellular organism , chromosome organization ,meiotic cell cycle , M phase of meiotic cell cycle , chromosome organization involved in meiosis ,

Nucleus . 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.