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Gene Review

DR1  -  down-regulator of transcription 1, TBP...

Homo sapiens

Synonyms: Down-regulator of transcription 1, NC2, NC2-BETA, NC2-beta, Negative cofactor 2-beta, ...
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Disease relevance of DR1

  • In three independent studies, using serological tissue typing techniques, an increase of the HLA class II specificity DR1 has been found in patients with multiple basal cell carcinomas [1].
  • Hypoxia actively represses transcription by inducing negative cofactor 2 (Dr1/DrAP1) and blocking preinitiation complex assembly [2].
  • Rheumatoid arthritis (RA) is an autoimmune disease associated with the HLA-DR4 and DR1 alleles [3].
  • A hexamer sequence of proteus haemolysin spanning residues 32-37 (ESRRAL) has been identified which resembles biochemically, and discriminates by charge, between HLA types associated with RA (DR1, Dw4, Dw14, Dw15), and those not linked with the disease (Dw10, Dw13) [4].
  • Rheumatoid arthritis (RA) is a chronic inflammatory joint disease associated with HLA-DR genes that share amino acid sequence motif QKRAA/QRRAA from position 70 to 74 in the third hypervariable region of DR1 molecule [5].

High impact information on DR1


Chemical compound and disease context of DR1


Biological context of DR1


Anatomical context of DR1

  • Human fibroblast cell lines (M1) coexpressing DR1 were transfected with these cDNAs and used in mixed lymphocyte reactions and flow cytometric studies in vitro [14].
  • The target autoantigen(s) in RA is unknown, but type II collagen (CII) is a candidate, and the DR4- and DR1-restricted immunodominant T cell epitope in this protein corresponds to amino acids 261-273 (CII 261-273) [3].
  • The development of the autoimmune arthritis was accompanied by strong DR1-restricted T and B cell responses to hCII [15].
  • Gold recognition did not require active antigen processing since specific proliferation was not affected by glutaraldehyde fixation of the DR1 homozygous antigen presenting cells [16].
  • The frequency of HLA antigens was studied in 28 patients with knee joint arthritis; this group was characterized by elevated frequencies of HLA-A2 and DR1 [17].

Associations of DR1 with chemical compounds

  • Potential anchor residues at P6 and P9 of the CII peptide are both Gly, and the lack of side chains at these positions appears to result in both a narrower binding groove with the peptide protruding out of the groove at this end of the DR1 molecule [18].
  • The association of DR4 with more severe disease and DR1 and DR2 with mild disease was confirmed but no associations were found between the presence of DQw7, Dw14, C4A or C4B null alleles and articular disease severity [19].
  • Variants of DR1 (DR1.2) or DR4 (Dw13.1, Dw14.1) with valine at position 86 appeared less able to confer risk for RA [20].
  • Relative risk was also associated with DR1.1, the common white DR1 (Dw1) type, which has a third hypervariable region amino acid sequence similar to some forms of DR4 and has glycine at position 86 [20].
  • No differences were seen in testosterone levels between DR1 or DR4 RA patients compared to those without these antigens [21].

Physical interactions of DR1

  • Negative co-factor 2 (NC2) regulates transcription of the class II genes through binding to TFIID and inhibition of pre-initiation complex formation [22].
  • In the absence of the tethering domain, Dr1 interacts with its corepressor DRAP1, but this interaction is not functional [23].
  • Mutants that affect the ability of E4BP4 to bring about transcriptional repression are also deficient in their binding of Dr1 [24].
  • The NC2 subunits dimerize and bind to TATA binding protein (TBP)-promoter complexes via histone fold domains of the H2A-H2B type [22].
  • HLA-DRB6 is one of the human major histocompatibility complex (MHC) genes present in DR1, DR2, and DR10 haplotypes (approximately 26% of individuals) [25].

Regulatory relationships of DR1

  • All DR1-positive patients and controls carried the DQA1*0101 and DQB1*0501 alleles [1].
  • Binding of NC2 inhibits association of TFIIB with TBP-promoter complexes [22].
  • Our data suggest that NC2 controls TBP binding and maintenance on DNA that is largely independent of a canonical TATA sequence [26].
  • Irradiated SUM159PT/DR1/CD80 vaccines stimulate proliferation of non-HLA-DRB0101 peripheral blood mononuclear cells and present an exogenous DR1-restricted tetanus toxoid (TT) peptide, indicating that the transduced DRB0101 is functional [27].
  • METHODS--PBL from 25 patients with RA and 12 healthy controls were cultured with DR1/4 restricted peptides of the influenza haemagglutinin, amino acids 307-319 (HA) and matrix proteins, amino acids 17-29 (IM) [28].

Other interactions of DR1

  • The association of Dr1 with TBP results in repression of both basal and activated levels of transcription [6].
  • The enhancement of Dr1-mediated repression of transcription by DRAP1 requires the tethering domain [23].
  • An important argument in favor of this shared-epitope hypothesis has been the reported association between DR1 and RA in Israeli Jews [29].
  • From the molecular analysis of the other DRB1 polymorphic variants, we find a trend of positive association of DRB1*0101 in DR4-negative patients versus DR4-negative healthy controls and, in the group of DR4-negative and/or DR1-negative patients, a similar increase of DRB1*06 [30].
  • In all 20 DR1 haplotypes, the DRB1*0101 or 0102 allele was associated with DQA1*0101 and DQB1*0501, being identical to the Caucasian DR1 haplotypes [29].

Analytical, diagnostic and therapeutic context of DR1

  • Functional dissection of a human Dr1-DRAP1 repressor complex [23].
  • Japanese patients with schizophrenia (n = 266, DSM-III-R criteria) and Japanese controls (n = 283) were genotyped for DR1 and DR4 alleles using a combination of group-specific polymerase chain reaction (PCR) amplification and PCR-restriction fragment length polymorphism [31].
  • In chromatin immunoprecipitations, NC2 is found on a variety of human TATA-containing and TATA-less promoters [26].
  • The corresponding serotyping subclassification, however, showed a significantly lower frequency only for DRB1-DR1 (P = 0.01, RR = 0.3) [32].
  • With polymerase chain reaction amplification and sequence analysis to characterize the class II alleles, we identified a novel DQB1 allele on the DR1 haplotype and an unusual DQB1 allele on the DR2 haplotype [33].


  1. Multiple basal cell carcinomas: no association with HLA-DRB, HLA-DQA1 or HLA-DQB1 in Swedish patients. Emtestam, L., Wallberg, P., Aldener, A., Olerup, O. Br. J. Dermatol. (1996) [Pubmed]
  2. Hypoxia actively represses transcription by inducing negative cofactor 2 (Dr1/DrAP1) and blocking preinitiation complex assembly. Denko, N., Wernke-Dollries, K., Johnson, A.B., Hammond, E., Chiang, C.M., Barton, M.C. J. Biol. Chem. (2003) [Pubmed]
  3. Definition of MHC and T cell receptor contacts in the HLA-DR4restricted immunodominant epitope in type II collagen and characterization of collagen-induced arthritis in HLA-DR4 and human CD4 transgenic mice. Andersson, E.C., Hansen, B.E., Jacobsen, H., Madsen, L.S., Andersen, C.B., Engberg, J., Rothbard, J.B., McDevitt, G.S., Malmström, V., Holmdahl, R., Svejgaard, A., Fugger, L. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  4. Sequence similarity between HLA-DR1 and DR4 subtypes associated with rheumatoid arthritis and proteus/serratia membrane haemolysins. Ebringer, A., Cunningham, P., Ahmadi, K., Wrigglesworth, J., Hosseini, R., Wilson, C. Ann. Rheum. Dis. (1992) [Pubmed]
  5. NRAMP1 gene polymorphisms in patients with rheumatoid arthritis. Singal, D.P., Li, J., Zhu, Y., Zhang, G. Tissue Antigens (2000) [Pubmed]
  6. Dr1, a TATA-binding protein-associated phosphoprotein and inhibitor of class II gene transcription. Inostroza, J.A., Mermelstein, F.H., Ha, I., Lane, W.S., Reinberg, D. Cell (1992) [Pubmed]
  7. Antigen analog-major histocompatibility complexes act as antagonists of the T cell receptor. De Magistris, M.T., Alexander, J., Coggeshall, M., Altman, A., Gaeta, F.C., Grey, H.M., Sette, A. Cell (1992) [Pubmed]
  8. All-trans and 9-cis retinoic acid induction of CRABPII transcription is mediated by RAR-RXR heterodimers bound to DR1 and DR2 repeated motifs. Durand, B., Saunders, M., Leroy, P., Leid, M., Chambon, P. Cell (1992) [Pubmed]
  9. Association of class II sequences encoding DR1 and DQ5 specificities with hypersensitivity to chironomid allergen Chi t I. Tautz, C., Rihs, H.P., Thiele, A., Zwollo, P., Freidhoff, L.R., Marsh, D.G., Baur, X. J. Allergy Clin. Immunol. (1994) [Pubmed]
  10. DNA ribonucleases that are active against intracellular hepatitis B viral RNA targets. Asahina, Y., Ito, Y., Wu, C.H., Wu, G.Y. Hepatology (1998) [Pubmed]
  11. Evidence for cobinding of self- and allopeptides to human class II major histocompatibility antigen DR1 by energy transfer. Kropshofer, H., Max, H., Kalbacher, H. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  12. Molecular characterization of a recombinant HLA-DR1/DR2 haplotype. Bidwell, J.L., Bidwell, E.A., Dupont, E., Andrien, M., Bouillenne, C., Klouda, P.T., Bradley, B.A. Hum. Immunol. (1992) [Pubmed]
  13. Genomic localization of the human gene encoding Dr1, a negative modulator of transcription of class II and class III genes. Purrello, M., Di Pietro, C., Rapisarda, A., Viola, A., Corsaro, C., Motta, S., Grzeschik, K.H., Sichel, G. Cytogenet. Cell Genet. (1996) [Pubmed]
  14. Cross-species costimulation: relative contributions of CD80, CD86, and CD40. Rogers, N.J., Jackson, I.M., Jordan, W.J., Hawadle, M.A., Dorling, A., Lechler, R.I. Transplantation (2003) [Pubmed]
  15. An HLA-DR1 transgene confers susceptibility to collagen-induced arthritis elicited with human type II collagen. Rosloniec, E.F., Brand, D.D., Myers, L.K., Whittington, K.B., Gumanovskaya, M., Zaller, D.M., Woods, A., Altmann, D.M., Stuart, J.M., Kang, A.H. J. Exp. Med. (1997) [Pubmed]
  16. Gold-specific T cells in rheumatoid arthritis patients treated with gold. Romagnoli, P., Spinas, G.A., Sinigaglia, F. J. Clin. Invest. (1992) [Pubmed]
  17. Arthritis confined to knee joints. Synovial lymphocyte responses to microbial antigens correlate with distribution of HLA. Ford, D.K., da Roza, D.M., Ward, R.H. Arthritis Rheum. (1984) [Pubmed]
  18. Crystallographic Structure of a Rheumatoid Arthritis MHC Susceptibility Allele, HLA-DR1 (DRB1*0101), Complexed with the Immunodominant Determinant of Human Type II Collagen. Rosloniec, E.F., Ivey, R.A., Whittington, K.B., Kang, A.H., Park, H.W. J. Immunol. (2006) [Pubmed]
  19. Major histocompatibility complex variants and articular disease severity in rheumatoid arthritis. McMahon, M.J., Hillarby, M.C., Clarkson, R.W., Hollis, S., Grennan, D.M. Br. J. Rheumatol. (1993) [Pubmed]
  20. HLA-DR alleles with naturally occurring amino acid substitutions and risk for development of rheumatoid arthritis. Gao, X.J., Olsen, N.J., Pincus, T., Stastny, P. Arthritis Rheum. (1990) [Pubmed]
  21. Free and serum testosterone levels in 276 males: a comparative study of rheumatoid arthritis, ankylosing spondylitis and healthy controls. Spector, T.D., Ollier, W., Perry, L.A., Silman, A.J., Thompson, P.W., Edwards, A. Clin. Rheumatol. (1989) [Pubmed]
  22. A mechanism for repression of class II gene transcription through specific binding of NC2 to TBP-promoter complexes via heterodimeric histone fold domains. Goppelt, A., Stelzer, G., Lottspeich, F., Meisterernst, M. EMBO J. (1996) [Pubmed]
  23. Functional dissection of a human Dr1-DRAP1 repressor complex. Yeung, K., Kim, S., Reinberg, D. Mol. Cell. Biol. (1997) [Pubmed]
  24. Protein-protein interaction between the transcriptional repressor E4BP4 and the TBP-binding protein Dr1. Cowell, I.G., Hurst, H.C. Nucleic Acids Res. (1996) [Pubmed]
  25. Transcription and weak expression of HLA-DRB6: a gene with anomalies in exon 1 and other regions. Fernandez-Soria, V.M., Morales, P., Castro, M.J., Suarez, B., Recio, M.J., Moreno, M.A., Paz-Artal, E., Arnaiz-Villena, A. Immunogenetics (1998) [Pubmed]
  26. Efficient binding of NC2.TATA-binding protein to DNA in the absence of TATA. Gilfillan, S., Stelzer, G., Piaia, E., Hofmann, M.G., Meisterernst, M. J. Biol. Chem. (2005) [Pubmed]
  27. Activation of tumor-specific CD4(+) T lymphocytes by major histocompatibility complex class II tumor cell vaccines: a novel cell-based immunotherapy. Dissanayake, S.K., Thompson, J.A., Bosch, J.J., Clements, V.K., Chen, P.W., Ksander, B.R., Ostrand-Rosenberg, S. Cancer Res. (2004) [Pubmed]
  28. Lymphocyte responses to DR1/4 restricted peptides in rheumatoid arthritis. Skinner, M.A., Watson, L., Geursen, A., Tan, P.L. Ann. Rheum. Dis. (1994) [Pubmed]
  29. HLA-DR1 and rheumatoid arthritis in Israeli Jews: sequencing reveals that DRB1*0102 is the predominant HLA-DR1 subtype. de Vries, N., Rønningen, K.S., Tilanus, M.G., Bouwens-Rombouts, A., Segal, R., Egeland, T., Thorsby, E., van de Putte, L.B., Brautbar, C. Tissue Antigens (1993) [Pubmed]
  30. Analysis of HLA DP, DQ, and DR alleles in adult Italian rheumatoid arthritis patients. Angelini, G., Morozzi, G., Delfino, L., Pera, C., Falco, M., Marcolongo, R., Giannelli, S., Ratti, G., Ricci, S., Fanetti, G. Hum. Immunol. (1992) [Pubmed]
  31. Evidence supporting an association between the DRB1 gene and schizophrenia in Japanese. Arinami, T., Otsuka, Y., Hamaguchi, H., Itokawa, M., Aoki, J., Shibuya, H., Okubo, Y., Iwawaki, A., Ota, K., Enguchi, H., Tagaya, H., Yano, S., Shimizu, H., Toru, M. Schizophr. Res. (1998) [Pubmed]
  32. HLA-DRB1*0101 and *0405 as protective alleles in Japanese patients with renal cell carcinoma. Ozdemir, E., Kakehi, Y., Nakamura, E., Kinoshita, H., Terachi, T., Okada, Y., Yoshida, O. Cancer Res. (1997) [Pubmed]
  33. Implication of specific DQB1 alleles in genetic susceptibility and resistance by identification of IDDM siblings with novel HLA-DQB1 allele and unusual DR2 and DR1 haplotypes. Erlich, H.A., Griffith, R.L., Bugawan, T.L., Ziegler, R., Alper, C., Eisenbarth, G. Diabetes (1991) [Pubmed]
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