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FANCA  -  Fanconi anemia, complementation group A

Homo sapiens

 
 
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Disease relevance of FANCA

 

Psychiatry related information on FANCA

  • Because FA cells are sensitive to mitomycin C (MMC), FA gene products could be involved in cellular defense mechanisms [3].
  • This study enables us to define this clinically heterogeneous disorder genotypically to better predict clinical outcome and aid decision-making regarding major therapeutic modalities for a subset of FA patients [5].
  • Eleven XP blood relatives (out of 1,100) were found with moderate or severe unexplained mental retardation, a significant excess compared to the FA and A-T families (3/1,439) [6].
  • Heterozygous carriers of an ataxia-telangiectasia (A-T), Fanconi anemia (FA), or xeroderma pigmentosum (XP) gene may be predisposed to some of the same congenital malformations or developmental disabilities that are common among homozygotes [6].
  • Pilots who attended FAA Safety Clinics tended to have a more internal locus of control than those who did not [7].
 

High impact information on FANCA

  • Fanconi anemia (FA) and ataxia telangiectasia (AT) are clinically distinct autosomal recessive disorders characterized by spontaneous chromosome breakage and hematological cancers [8].
  • The frameshift mutation 1615delG in FANCA was compensated by two additional single base-pair deletions (1637delA and 1641delT); another FANCA frameshift mutation, 3559insG, was compensated by 3580insCGCTG; and a missense mutation in FANCC(1749T-->G, Leu496Arg) was altered by 1748C-->T, creating a cysteine codon [9].
  • Although in all three cases the predicted proteins were different from wild type, their cDNAs complemented the characteristic hypersensitivity of FA cells to crosslinking agents, thus establishing a functional correction to wild type [9].
  • Here we document for the first time functional correction of a pathogenic microdeletion, microinsertion and missense mutation in homozygous Fanconi anaemia (FA) patients resulting from compensatory secondary sequence alterations in cis [9].
  • Fanconi anemia (FA) is an autosomal recessive disease with diverse clinical symptoms including developmental anomalies, bone marrow failure and early occurrence of malignancies [10].
 

Chemical compound and disease context of FANCA

 

Biological context of FANCA

  • The interaction does not depend on DNA damage, thus FANCA and BRCA1 are constitutively interacting [16].
  • The G2/M checkpoint-mediated arrest of the cell cycle is critical for the prevention of both apoptosis and the accumulation of cells with rereplicated DNA, because the loss of ATR, BRCA1, or FANCA promotes apoptosis and suppresses the accumulation [17].
  • The accumulation of cells with rereplicated DNA is restored by the artificial induction of a G2-phase arrest even when ATR, BRCA1, or FANCA is absent [17].
  • All exons of FANCA and FANCG were sequenced, and no mutations were found [2].
  • Patient-derived mutant forms of FANCA, containing an intact NLS sequence but point mutations in the carboxy-terminal leucine zipper region, bound FANCG in the cytoplasm [18].
 

Anatomical context of FANCA

 

Associations of FANCA with chemical compounds

 

Physical interactions of FANCA

  • We report that the protein encoded by the gene mutated in complementation group G (FANCG) localizes to the cytoplasm and nucleus of the cell and assembles in a molecular complex with the FANCA protein, both in vivo and in vitro [1].
  • BRCA1 interacts directly with the Fanconi anemia protein FANCA [16].
  • We demonstrate a direct interaction between FANCB and FANCL and that a complex of these proteins binds FANCA [27].
  • FANCC is found in both the cytoplasmic and the nuclear compartments and interacts with certain other FA complementation group proteins as well as with non-FA proteins [28].
  • 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 [29].
 

Regulatory relationships of FANCA

  • The FA nuclear complex regulates the mono-ubiquitination of FANCD2 in response to DNA damage, resulting in targeting of this protein into nuclear foci [30].
  • Both ATR and BRCA1 are required to activate the FA pathway [17].
  • However, a high level of activation was found when FANCA was co-expressed with FANCG, indicating strong, direct interaction between these proteins [31].
  • The observed specific changes in gene expression suggest that FANCC regulates specifically myeloid differentiation and unmasks a previously unsuspected anti-inflammatory role for the FA proteins [32].
  • At present, it is poorly understood how the nuclear accumulation of FANCE is regulated and therefore we investigated the nuclear localization of this FA protein [33].
 

Other interactions of FANCA

  • In normal (non-FA) cells, FANCD2 is monoubiquitinated in response to DNA damage and is targeted to nuclear foci (dots) [34].
  • Here we report the identification, by complementation cloning, of the gene mutated in FA complementation group E (FANCE) [35].
  • Neither FANCA nor FANCC was found to interact with itself [36].
  • Among the known FANC proteins, we find evidence for direct interaction only between the FANCA protein and BRCA1 [16].
  • Mutations in BRCA2, which participates in homologous recombination (HR), are the underlying cause in some FA patients [21].
 

Analytical, diagnostic and therapeutic context of FANCA

References

  1. A physical complex of the Fanconi anemia proteins FANCG/XRCC9 and FANCA. Waisfisz, Q., de Winter, J.P., Kruyt, F.A., de Groot, J., van der Weel, L., Dijkmans, L.M., Zhi, Y., Arwert, F., Scheper, R.J., Youssoufian, H., Hoatlin, M.E., Joenje, H. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  2. Acquired FANCA dysfunction and cytogenetic instability in adult acute myelogenous leukemia. Lensch, M.W., Tischkowitz, M., Christianson, T.A., Reifsteck, C.A., Speckhart, S.A., Jakobs, P.M., O'Dwyer, M.E., Olson, S.B., Le Beau, M.M., Hodgson, S.V., Mathew, C.G., Larson, R.A., Bagby, G.C. Blood (2003) [Pubmed]
  3. Resistance to mitomycin C requires direct interaction between the Fanconi anemia proteins FANCA and FANCG in the nucleus through an arginine-rich domain. Kruyt, F.A., Abou-Zahr, F., Mok, H., Youssoufian, H. J. Biol. Chem. (1999) [Pubmed]
  4. FANCD2 associated with sporadic breast cancer risk. Barroso, E., Milne, R.L., Fernández, L.P., Zamora, P., Arias, J.I., Benítez, J., Ribas, G. Carcinogenesis (2006) [Pubmed]
  5. Phenotypic consequences of mutations in the Fanconi anemia FAC gene: an International Fanconi Anemia Registry study. Gillio, A.P., Verlander, P.C., Batish, S.D., Giampietro, P.F., Auerbach, A.D. Blood (1997) [Pubmed]
  6. Congenital malformations and developmental disabilities in ataxia-telangiectasia, Fanconi anemia, and xeroderma pigmentosum families. Welshimer, K., Swift, M. Am. J. Hum. Genet. (1982) [Pubmed]
  7. Locus of control, self-serving biases, and attitudes towards safety in general aviation pilots. Wichman, H., Ball, J. Aviation, space, and environmental medicine. (1983) [Pubmed]
  8. 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]
  9. Spontaneous functional correction of homozygous fanconi anaemia alleles reveals novel mechanistic basis for reverse mosaicism. Waisfisz, Q., Morgan, N.V., Savino, M., de Winter, J.P., van Berkel, C.G., Hoatlin, M.E., Ianzano, L., Gibson, R.A., Arwert, F., Savoia, A., Mathew, C.G., Pronk, J.C., Joenje, H. Nat. Genet. (1999) [Pubmed]
  10. The Fanconi anaemia group G gene FANCG is identical with XRCC9. de Winter, J.P., Waisfisz, Q., Rooimans, M.A., van Berkel, C.G., Bosnoyan-Collins, L., Alon, N., Carreau, M., Bender, O., Demuth, I., Schindler, D., Pronk, J.C., Arwert, F., Hoehn, H., Digweed, M., Buchwald, M., Joenje, H. Nat. Genet. (1998) [Pubmed]
  11. A cytoplasmic serine protein kinase binds and may regulate the Fanconi anemia protein FANCA. Yagasaki, H., Adachi, D., Oda, T., Garcia-Higuera, I., Tetteh, N., D'Andrea, A.D., Futaki, M., Asano, S., Yamashita, T. Blood (2001) [Pubmed]
  12. Promoter hypermethylation of FANCF: disruption of Fanconi Anemia-BRCA pathway in cervical cancer. Narayan, G., Arias-Pulido, H., Nandula, S.V., Basso, K., Sugirtharaj, D.D., Vargas, H., Mansukhani, M., Villella, J., Meyer, L., Schneider, A., Gissmann, L., Dürst, M., Pothuri, B., Murty, V.V. Cancer Res. (2004) [Pubmed]
  13. Chemosensitizing tumor cells by targeting the Fanconi anemia pathway with an adenovirus overexpressing dominant-negative FANCA. Ferrer, M., de Winter, J.P., Mastenbroek, D.C., Curiel, D.T., Gerritsen, W.R., Giaccone, G., Kruyt, F.A. Cancer Gene Ther. (2004) [Pubmed]
  14. The Fanconi anemia complementation group C protein corrects DNA interstrand cross-link-specific apoptosis in HSC536N cells. Marathi, U.K., Howell, S.R., Ashmun, R.A., Brent, T.P. Blood (1996) [Pubmed]
  15. The FA/BRCA pathway is involved in melphalan-induced DNA interstrand cross-link repair and accounts for melphalan resistance in multiple myeloma cells. Chen, Q., Van der Sluis, P.C., Boulware, D., Hazlehurst, L.A., Dalton, W.S. Blood (2005) [Pubmed]
  16. BRCA1 interacts directly with the Fanconi anemia protein FANCA. Folias, A., Matkovic, M., Bruun, D., Reid, S., Hejna, J., Grompe, M., D'Andrea, A., Moses, R. Hum. Mol. Genet. (2002) [Pubmed]
  17. An ATR- and BRCA1-mediated Fanconi anemia pathway is required for activating the G2/M checkpoint and DNA damage repair upon rereplication. Zhu, W., Dutta, A. Mol. Cell. Biol. (2006) [Pubmed]
  18. The fanconi anemia proteins FANCA and FANCG stabilize each other and promote the nuclear accumulation of the Fanconi anemia complex. Garcia-Higuera, I., Kuang, Y., Denham, J., D'Andrea, A.D. Blood (2000) [Pubmed]
  19. A patient-derived mutant form of the Fanconi anemia protein, FANCA, is defective in nuclear accumulation. Kupfer, G., Naf, D., Garcia-Higuera, I., Wasik, J., Cheng, A., Yamashita, T., Tipping, A., Morgan, N., Mathew, C.G., D'Andrea, A.D. Exp. Hematol. (1999) [Pubmed]
  20. The molecular biology of Fanconi anemia. Tamary, H., Bar-Yam, R., Zemach, M., Dgany, O., Shalmon, L., Yaniv, I. Isr. Med. Assoc. J. (2002) [Pubmed]
  21. Fanconi anemia FANCG protein in mitigating radiation- and enzyme-induced DNA double-strand breaks by homologous recombination in vertebrate cells. Yamamoto, K., Ishiai, M., Matsushita, N., Arakawa, H., Lamerdin, J.E., Buerstedde, J.M., Tanimoto, M., Harada, M., Thompson, L.H., Takata, M. Mol. Cell. Biol. (2003) [Pubmed]
  22. Evolutionary clues to the molecular function of fanconi anemia genes. Blom, E., van de Vrugt, H.J., de Winter, J.P., Arwert, F., Joenje, H. Acta Haematol. (2002) [Pubmed]
  23. Somatic mosaicism in Fanconi anemia: evidence of genotypic reversion in lymphohematopoietic stem cells. Gregory, J.J., Wagner, J.E., Verlander, P.C., Levran, O., Batish, S.D., Eide, C.R., Steffenhagen, A., Hirsch, B., Auerbach, A.D. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  24. Identification of multiple nuclear export sequences in Fanconi anemia group A protein that contribute to CRM1-dependent nuclear export. Ferrer, M., Rodríguez, J.A., Spierings, E.A., de Winter, J.P., Giaccone, G., Kruyt, F.A. Hum. Mol. Genet. (2005) [Pubmed]
  25. Oxidative stress/damage induces multimerization and interaction of Fanconi anemia proteins. Park, S.J., Ciccone, S.L., Beck, B.D., Hwang, B., Freie, B., Clapp, D.W., Lee, S.H. J. Biol. Chem. (2004) [Pubmed]
  26. Human alpha spectrin II and the FANCA, FANCC, and FANCG proteins bind to DNA containing psoralen interstrand cross-links. McMahon, L.W., Sangerman, J., Goodman, S.R., Kumaresan, K., Lambert, M.W. Biochemistry (2001) [Pubmed]
  27. Evidence for subcomplexes in the Fanconi anemia pathway. Medhurst, A.L., Laghmani, e.l. .H., Steltenpool, J., Ferrer, M., Fontaine, C., de Groot, J., Rooimans, M.A., Scheper, R.J., Meetei, A.R., Wang, W., Joenje, H., de Winter, J.P. Blood (2006) [Pubmed]
  28. Posttranscriptional cell cycle-dependent regulation of human FANCC expression. Heinrich, M.C., Silvey, K.V., Stone, S., Zigler, A.J., Griffith, D.J., Montalto, M., Chai, L., Zhi, Y., Hoatlin, M.E. Blood (2000) [Pubmed]
  29. 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]
  30. Fanconi anemia and DNA repair. Grompe, M., D'Andrea, A. Hum. Mol. Genet. (2001) [Pubmed]
  31. Investigation of Fanconi anemia protein interactions by yeast two-hybrid analysis. Huber, P.A., Medhurst, A.L., Youssoufian, H., Mathew, C.G. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  32. Fanconi anemia C gene product regulates expression of genes involved in differentiation and inflammation. Zanier, R., Briot, D., Dugas du Villard, J.A., Sarasin, A., Rosselli, F. Oncogene (2004) [Pubmed]
  33. 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]
  34. 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]
  35. Isolation of a cDNA representing the Fanconi anemia complementation group E gene. de Winter, J.P., Léveillé, F., van Berkel, C.G., Rooimans, M.A., van Der Weel, L., Steltenpool, J., Demuth, I., Morgan, N.V., Alon, N., Bosnoyan-Collins, L., Lightfoot, J., Leegwater, P.A., Waisfisz, Q., Komatsu, K., Arwert, F., Pronk, J.C., Mathew, C.G., Digweed, M., Buchwald, M., Joenje, H. Am. J. Hum. Genet. (2000) [Pubmed]
  36. Strong FANCA/FANCG but weak FANCA/FANCC interaction in the yeast 2-hybrid system. Reuter, T., Herterich, S., Bernhard, O., Hoehn, H., Gross, H.J. Blood (2000) [Pubmed]
  37. SNX5, a new member of the sorting nexin family, binds to the Fanconi anemia complementation group A protein. Otsuki, T., Kajigaya, S., Ozawa, K., Liu, J.M. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  38. Molecular characterization of three novel Fanconi anemia mutations in Israeli Arabs. Tamary, H., Dgany, O., Toledano, H., Shalev, Z., Krasnov, T., Shalmon, L., Schechter, T., Bercovich, D., Attias, D., Laor, R., Koren, A., Yaniv, I. Eur. J. Haematol. (2004) [Pubmed]
 
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