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FANCD2  -  Fanconi anemia, complementation group D2

Homo sapiens

Synonyms: FA-D2, FA4, FACD, FAD, FAD2, ...
 
 
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Disease relevance of FANCD2

 

Psychiatry related information on FANCD2

 

High impact information on FANCD2

 

Chemical compound and disease context of FANCD2

 

Biological context of FANCD2

 

Anatomical context of FANCD2

  • In addition, using patient-derived FA cell lines and siRNA targeting FANCD2, we demonstrate a functional requirement for the FA pathway in response to low doses of APH: a replicative stress treatment known to result in chromosome breakage at common fragile sites [14].
  • Strikingly, FANCD2 monoubiquitination was detected in peripheral blood lymphocytes (PBLs) in 8 (15%) patients [15].
  • Furthermore, ablation of the RING finger domains of either BRCA1 or BARD1 in the chicken B cell line DT40 also leaves FANCD2 modification intact [16].
  • In stably transfected FANCD2(-/-) fibroblasts, FANCD2-44 and FANCD2-43 proteins were monoubiquitinated on K561 [17].
  • Monoubiquitination of FANCD2 was normal in other bone marrow failure syndromes and chromosomal breakage syndromes [18].
 

Associations of FANCD2 with chemical compounds

  • Mono-ubiquitination of FANCD2, a measure of the function of this pathway, and cisplatin resistance were restored by functional complementation with FANCF, a gene that is upstream in this pathway [19].
  • They are also impaired in ubiquitination of FANCD2 after HU treatment, which is ATR dependent [20].
  • Furthermore, the formation of FANCD2 foci is restricted to a subpopulation of cells, which can be labeled by bromodeoxyuridine incorporation [21].
  • Mutation of this tryptophan in the FANCL PHD significantly impairs in vivo mono-ubiquitination of FANCD2 and in vitro auto-ubiquitination activity, and partially impairs restoration of mitomycin C resistance [22].
  • Descriptions of phenotypic features were available for six additional recently defined 14q-linked FAD kindreds: the findings in four of them (FAD4, FAD2, A, B) indicated a relatively consistently shared 14qFAD phenotype, conforming closely with the specific clinical and neuropathological characteristics noted in the L family [23].
 

Physical interactions of FANCD2

  • Active FANCD2 then interacts with BRCA1 and forms discrete nuclear foci [3].
  • Six of the eight proteins encoded by the known FA genes form a nuclear complex which is required for the monoubiquitination of the FANCD2 protein [12].
  • ATR couples FANCD2 monoubiquitination to the DNA-damage response [24].
  • Here we show that menin specifically interacts with FANCD2, a protein encoded by a gene involved in DNA repair and mutated in patients with an inherited cancer-prone syndrome, Fanconi anemia [25].
  • Finally, we show that the region of FANCE interacting with FANCC appears to be different from the region involved in binding FANCD2 [26].
 

Enzymatic interactions of FANCD2

  • ATR phosphorylates FANCD2 on these two sites, thereby promoting FANCD2 monoubiquitination and enhancing cellular resistance to DNA cross-linking agents [27].
 

Regulatory relationships of FANCD2

 

Other interactions of FANCD2

  • Here we show that the recently identified FANCE protein is part of this nuclear complex, binding both FANCC and FANCD2 [30].
  • Direct interaction of FANCD2 with BRCA2 in DNA damage response pathways [12].
  • Using immunoblotting, NM3 and UV40 were found not to express the active monoubiquitinated isoform of the FANCD2 protein, although expression of the FANCD-L isoform was restored in the FANCG cDNA transformants, correlating with the correction of mutagen-sensitivity [13].
  • We provide evidence that BLM and FANCD2 colocalise and co-immunoprecipitate following treatment with either DNA crosslinkers or agents inducing replication arrest [31].
  • Furthermore, USP1 physically associates with FANCD2, and the proteins colocalize in chromatin after DNA damage [32].
 

Analytical, diagnostic and therapeutic context of FANCD2

References

  1. The BRCA1-interacting helicase BRIP1 is deficient in Fanconi anemia. Levran, O., Attwooll, C., Henry, R.T., Milton, K.L., Neveling, K., Rio, P., Batish, S.D., Kalb, R., Velleuer, E., Barral, S., Ott, J., Petrini, J., Schindler, D., Hanenberg, H., Auerbach, A.D. Nat. Genet. (2005) [Pubmed]
  2. Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway. Garcia-Higuera, I., Taniguchi, T., Ganesan, S., Meyn, M.S., Timmers, C., Hejna, J., Grompe, M., D'Andrea, A.D. Mol. Cell (2001) [Pubmed]
  3. The Fanconi anaemia genome stability and tumour suppressor network. Bogliolo, M., Cabré, O., Callén, E., Castillo, V., Creus, A., Marcos, R., Surrallés, J. Mutagenesis (2002) [Pubmed]
  4. Convergence of the fanconi anemia and ataxia telangiectasia signaling pathways. Taniguchi, T., Garcia-Higuera, I., Xu, B., Andreassen, P.R., Gregory, R.C., Kim, S.T., Lane, W.S., Kastan, M.B., D'Andrea, A.D. Cell (2002) [Pubmed]
  5. Interaction of FANCD2 and NBS1 in the DNA damage response. Nakanishi, K., Taniguchi, T., Ranganathan, V., New, H.V., Moreau, L.A., Stotsky, M., Mathew, C.G., Kastan, M.B., Weaver, D.T., D'Andrea, A.D. Nat. Cell Biol. (2002) [Pubmed]
  6. Inherited neurodegenerative diseases and transgenic models. Price, D.L., Becher, M.W., Wong, P.C., Borchelt, D.R., Lee, M.K., Sisodia, S.S. Brain Pathol. (1996) [Pubmed]
  7. A human ortholog of archaeal DNA repair protein Hef is defective in Fanconi anemia complementation group M. Meetei, A.R., Medhurst, A.L., Ling, C., Xue, Y., Singh, T.R., Bier, P., Steltenpool, J., Stone, S., Dokal, I., Mathew, C.G., Hoatlin, M., Joenje, H., de Winter, J.P., Wang, W. Nat. Genet. (2005) [Pubmed]
  8. X-linked inheritance of Fanconi anemia complementation group B. Meetei, A.R., Levitus, M., Xue, Y., Medhurst, A.L., Zwaan, M., Ling, C., Rooimans, M.A., Bier, P., Hoatlin, M., Pals, G., de Winter, J.P., Wang, W., Joenje, H. Nat. Genet. (2004) [Pubmed]
  9. A novel ubiquitin ligase is deficient in Fanconi anemia. Meetei, A.R., de Winter, J.P., Medhurst, A.L., Wallisch, M., Waisfisz, Q., van de Vrugt, H.J., Oostra, A.B., Yan, Z., Ling, C., Bishop, C.E., Hoatlin, M.E., Joenje, H., Wang, W. Nat. Genet. (2003) [Pubmed]
  10. Chemosensitization to cisplatin by inhibitors of the Fanconi anemia/BRCA pathway. Chirnomas, D., Taniguchi, T., de la Vega, M., Vaidya, A.P., Vasserman, M., Hartman, A.R., Kennedy, R., Foster, R., Mahoney, J., Seiden, M.V., D'Andrea, A.D. Mol. Cancer Ther. (2006) [Pubmed]
  11. Human Fanconi anemia monoubiquitination pathway promotes homologous DNA repair. Nakanishi, K., Yang, Y.G., Pierce, A.J., Taniguchi, T., Digweed, M., D'Andrea, A.D., Wang, Z.Q., Jasin, M. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  12. Direct interaction of FANCD2 with BRCA2 in DNA damage response pathways. Hussain, S., Wilson, J.B., Medhurst, A.L., Hejna, J., Witt, E., Ananth, S., Davies, A., Masson, J.Y., Moses, R., West, S.C., de Winter, J.P., Ashworth, A., Jones, N.J., Mathew, C.G. Hum. Mol. Genet. (2004) [Pubmed]
  13. 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, J.B., Johnson, M.A., Stuckert, A.P., Trueman, K.L., May, S., Bryant, P.E., Meyn, R.E., D'Andrea, A.D., Jones, N.J. Carcinogenesis (2001) [Pubmed]
  14. The Fanconi anemia pathway is required for the DNA replication stress response and for the regulation of common fragile site stability. Howlett, N.G., Taniguchi, T., Durkin, S.G., D'Andrea, A.D., Glover, T.W. Hum. Mol. Genet. (2005) [Pubmed]
  15. Detection of somatic mosaicism and classification of Fanconi anemia patients by analysis of the FA/BRCA pathway. Soulier, J., Leblanc, T., Larghero, J., Dastot, H., Shimamura, A., Guardiola, P., Esperou, H., Ferry, C., Jubert, C., Feugeas, J.P., Henri, A., Toubert, A., Socié, G., Baruchel, A., Sigaux, F., D'Andrea, A.D., Gluckman, E. Blood (2005) [Pubmed]
  16. BRCA1-independent ubiquitination of FANCD2. Vandenberg, C.J., Gergely, F., Ong, C.Y., Pace, P., Mallery, D.L., Hiom, K., Patel, K.J. Mol. Cell (2003) [Pubmed]
  17. Regulated interaction of the Fanconi anemia protein, FANCD2, with chromatin. Montes de Oca, R., Andreassen, P.R., Margossian, S.P., Gregory, R.C., Taniguchi, T., Wang, X., Houghtaling, S., Grompe, M., D'Andrea, A.D. Blood (2005) [Pubmed]
  18. A novel diagnostic screen for defects in the Fanconi anemia pathway. Shimamura, A., de Oca, R.M., Svenson, J.L., Haining, N., Moreau, L.A., Nathan, D.G., D'Andrea, A.D. Blood (2002) [Pubmed]
  19. Disruption of the Fanconi anemia-BRCA pathway in cisplatin-sensitive ovarian tumors. Taniguchi, T., Tischkowitz, M., Ameziane, N., Hodgson, S.V., Mathew, C.G., Joenje, H., Mok, S.C., D'Andrea, A.D. Nat. Med. (2003) [Pubmed]
  20. Nbs1 is required for ATR-dependent phosphorylation events. Stiff, T., Reis, C., Alderton, G.K., Woodbine, L., O'Driscoll, M., Jeggo, P.A. EMBO J. (2005) [Pubmed]
  21. Repair kinetics of genomic interstrand DNA cross-links: evidence for DNA double-strand break-dependent activation of the Fanconi anemia/BRCA pathway. Rothfuss, A., Grompe, M. Mol. Cell. Biol. (2004) [Pubmed]
  22. The WD40 Repeats of FANCL Are Required for Fanconi Anemia Core Complex Assembly. Gurtan, A.M., Stuckert, P., D'Andrea, A.D. J. Biol. Chem. (2006) [Pubmed]
  23. Phenotype of chromosome 14-linked familial Alzheimer's disease in a large kindred. Lampe, T.H., Bird, T.D., Nochlin, D., Nemens, E., Risse, S.C., Sumi, S.M., Koerker, R., Leaird, B., Wier, M., Raskind, M.A. Ann. Neurol. (1994) [Pubmed]
  24. ATR couples FANCD2 monoubiquitination to the DNA-damage response. Andreassen, P.R., D'Andrea, A.D., Taniguchi, T. Genes Dev. (2004) [Pubmed]
  25. Menin associates with FANCD2, a protein involved in repair of DNA damage. Jin, S., Mao, H., Schnepp, R.W., Sykes, S.M., Silva, A.C., D'Andrea, A.D., Hua, X. Cancer Res. (2003) [Pubmed]
  26. The nuclear accumulation of the Fanconi anemia protein FANCE depends on FANCC. Léveillé, F., Ferrer, M., Medhurst, A.L., Laghmani, e.l. .H., Rooimans, M.A., Bier, P., Steltenpool, J., Titus, T.A., Postlethwait, J.H., Hoatlin, M.E., Joenje, H., de Winter, J.P. DNA Repair (Amst.) (2006) [Pubmed]
  27. Phosphorylation of FANCD2 on two novel sites is required for mitomycin C resistance. Ho, G.P., Margossian, S., Taniguchi, T., D'Andrea, A.D. Mol. Cell. Biol. (2006) [Pubmed]
  28. Fanconi anemia and DNA repair. Grompe, M., D'Andrea, A. Hum. Mol. Genet. (2001) [Pubmed]
  29. FANCD2 protein is expressed in proliferating cells of human tissues that are cancer-prone in Fanconi anaemia. Hölzel, M., van Diest, P.J., Bier, P., Wallisch, M., Hoatlin, M.E., Joenje, H., de Winter, J.P. J. Pathol. (2003) [Pubmed]
  30. FANCE: the link between Fanconi anaemia complex assembly and activity. Pace, P., Johnson, M., Tan, W.M., Mosedale, G., Sng, C., Hoatlin, M., de Winter, J., Joenje, H., Gergely, F., Patel, K.J. EMBO J. (2002) [Pubmed]
  31. BLM and the FANC proteins collaborate in a common pathway in response to stalled replication forks. Pichierri, P., Franchitto, A., Rosselli, F. EMBO J. (2004) [Pubmed]
  32. The deubiquitinating enzyme USP1 regulates the Fanconi anemia pathway. Nijman, S.M., Huang, T.T., Dirac, A.M., Brummelkamp, T.R., Kerkhoven, R.M., D'Andrea, A.D., Bernards, R. Mol. Cell (2005) [Pubmed]
  33. Variation in cisplatinum sensitivity is not associated with Fanconi Anemia/BRCA pathway inactivation in head and neck squamous cell carcinoma cell lines. Snyder, E.R., Ricker, J.L., Chen, Z., Waes, C.V. Cancer Lett. (2007) [Pubmed]
  34. FANCD2 expression in advanced non-small-cell lung cancer and response to platinum-based chemotherapy. Ferrer, M., Span, S.W., Vischioni, B., Oudejans, J.J., van Diest, P.J., de Winter, J.P., Giaccone, G., Kruyt, F.A. Clinical lung cancer. (2005) [Pubmed]
  35. Molecular cloning of the Drosophila Fanconi anaemia gene FANCD2 cDNA. Castillo, V., Cabré, O., Marcos, R., Surrallés, J. DNA Repair (Amst.) (2003) [Pubmed]
  36. Cloning and Sequence Analysis of Maize FAD2 Gene. Tao, F., Zhu, S.W., Fan, J., Cheng, B.J. Zhi Wu Sheng Li Yu Fen Zi Sheng Wu Xue Xue Bao (2006) [Pubmed]
 
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