Alternative titles; symbols
HGNC Approved Gene Symbol: DR1
Cytogenetic location: 1p22.1 Genomic coordinates (GRCh38): 1:93,345,907-93,369,493 (from NCBI)
Several phosphoproteins interact with TBP, the TATA box-binding protein (600075). Among them, DR1 is a TBP-associated phosphoprotein that represses both basal and activated levels of transcription. Inostroza et al. (1992) biochemically characterized DR1 purified from HeLa cells and cloned the human gene from a HeLa cell cDNA library. The gene encodes a 176-amino acid polypeptide of 19 kD. They showed that DR1 is phosphorylated in vivo and that phosphorylation of DR1 affected its interaction with TBP.
Using Northern blot analysis, Inostroza et al. (1992) and Mermelstein et al. (1996) detected varying levels of 1.5- and 3.4-kb DR1 transcripts in all tissues examined. By Northern blot analysis of rat tissues, Purrello et al. (1996) detected a 3.6 kb mRNA in all tested tissues, with a second 1.8 kb message in testis. The highest level of expression was seen in testis.
Mermelstein et al. (1996) identified DR1-associated protein-1 (DRAP1; 602289), a corepressor of DR1 that enhances DR1-mediated repression of transcription. Mermelstein et al. (1996) immunodetected DR1 protein in all cell populations of the developing rat brain: actively dividing stem cells, nondividing migratory neurons, and nondividing, highly differentiated neurons. Based on the differential expression of DR1 and DRAP1 proteins in the developing rat brain, Mermelstein et al. (1996) suggested that DR1-mediated repression of transcription is higher in nondividing, highly differentiated cells than in actively dividing cells.
The DR1 protein contains 3 domains: a histone fold motif at the N terminus, a TBP-binding domain, and a glutamine- and alanine-rich region. Mermelstein et al. (1996) showed that the histone fold motif of DR1 is required for DR1-DRAP1 interaction. Both the TBP-binding domain and the glutamine- and alanine-rich region are required for DR1-mediated repression of transcription. Yeung et al. (1997) demonstrated that the TBP-binding domain has 2 functions: it tethers the DR1 repressor complex to the promoter by interacting with TBP, and it is required for the corepression activity of DRAP1, although it is not required for DR1-DRAP1 interaction. Yeung et al. (1997) determined that the glutamine- and alanine-rich region is the repressor domain of DR1 and that this domain interacts with TBP. Goppelt et al. (1996) proposed that binding of DR1 repressor complexes to TBP-promoter complexes establishes a mechanism in which an altered DNA conformation, together with the formation of higher order complexes, inhibits the assembly of the preinitiation complex and controls the rate of RNA polymerase II transcription.
Willy et al. (2000) identified an activity that was required for transcription of downstream promoter element (DPE)-containing core promoters in vitro. The purified factor was found to be the Drosophila homolog of the NC2 transcriptional repressor, also known as DR1-DRAP1. Drosophila Nc2 is composed of a 43-kD subunit homologous to DRAP1 (NC2-alpha) and a 22-kD subunit homologous to DR1 (NC2-beta). Purified recombinant Drosophila Nc2 activated DPE-driven promoters and repressed TATA-driven promoters. A mutant version of Drosophila Nc2 could activate DPE promoters but was unable to repress TATA promoters. Thus, the activation and repression functions are distinct. Willy et al. (2000) concluded that NC2 is a bifunctional basal transcription factor that differentially regulates gene transcription through DPE or TATA box motifs.
Using mass spectrometry, Wang et al. (2008) identified NC2-beta as a component of the ADA2A (TADA2A; 602276)-containing (ATAC) histone acetyltransferase complex in HeLa cells.
Rozet et al. (1996) determined that the DR1 gene contains 3 exons and spans 15 kb of genomic DNA.
Kamada et al. (2001) determined the x-ray structure of a ternary complex of NC2, TBP, and DNA at 2.6-angstrom resolution. The N termini of NC2-alpha and -beta resemble histones H2A (see 613499) and H2B (see 609904), respectively, and form a heterodimer that binds to the bent DNA double helix on the underside of the preformed TBP-DNA complex via electrostatic interactions. NC2-beta contributes to inhibition of TATA-dependent transcription through interactions of its C-terminal alpha helix with a conserved hydrophobic feature on the upper surface of TBP, which in turn positions the penultimate alpha helix of NC2-beta to block recognition of the TBP-DNA complex by transcription factor IIB (189963).
By fluorescence in situ hybridization, Rozet et al. (1996) mapped the DR1 gene to 1p22.1. Purrello et al. (1996) used somatic cell genetics and fluorescence in situ hybridization to map the DR1 gene to human chromosome region 1p21-p13. Southern blot analysis showed that the gene is present as a single copy in the genomes of all eukaryotes examined.
Kaplan et al. (1993) mapped an expressed sequence tag (EST) of the DR1 gene to the YAC contig encompassing the Stargardt disease locus (STGD; 248200) on 1p. Using SSCP analysis of genomic DNA amplified with specific primers in 10 controls and 35 unrelated patients with either Stargardt disease (26 patients) or late-onset fundus flavimaculatus, a condition allelic to STGD (9 patients), Rozet et al. (1996) found no mutation in the DR1 gene. Rozet et al. (1996) were not able to study the promoter of the gene, but the findings suggested that DR1 is not involved in Stargardt disease.
Goppelt, A., Stelzer, G., Lottspeich, F., Meisterernst, M. A mechanism for repression of class II gene transcription through specific binding of NC2 to TBP-promoter complexes via heterodimeric histone fold domains. EMBO J. 15: 3105-3116, 1996. [PubMed: 8670811]
Inostroza, J. A., Mermelstein, F. H., Ha, I., Lane, W. S., Reinberg, D. Dr1, a TATA-binding protein-associated phosphoprotein and inhibitor of class II gene transcription. Cell 70: 477-489, 1992. [PubMed: 1339312] [Full Text: https://doi.org/10.1016/0092-8674(92)90172-9]
Kamada, K., Shu, F., Chen, H., Malik, S., Stelzer, G., Roeder, R. G., Meisterernst, M., Burley, S. K. Crystal structure of negative cofactor 2 recognizing the TBP-DNA transcription complex. Cell 106: 71-81, 2001. [PubMed: 11461703] [Full Text: https://doi.org/10.1016/s0092-8674(01)00417-2]
Kaplan, J., Gerber, S., Larget-Piet, D., Rozet, J.-M., Dollfus, H., Dufier, J.-L., Odent, S., Postel-Vinay, A., Janin, N., Briard, M.-L., Frezal, J., Munnich, A. A gene for Stargardt's disease (fundus flavimaculatus) maps to the short arm of chromosome 1. Nature Genet. 5: 308-311, 1993. Note: Erratum: Nature Genet. 6: 214 only, 1994. [PubMed: 8275096] [Full Text: https://doi.org/10.1038/ng1193-308]
Mermelstein, F., Yeung, K., Cao, J., Inostroza, J. A., Erdjument-Bromage, H., Eagelson, K., Landsman, D., Levitt, P., Tempst, P., Reinberg, D. Requirement of a corepressor for Dr1-mediated repression of transcription. Genes Dev. 10: 1033-1048, 1996. [PubMed: 8608938] [Full Text: https://doi.org/10.1101/gad.10.8.1033]
Purrello, M., Di Pietro, C., Rapisarda, A., Viola, A., Corsaro, C., Motta, S., Grzeschik, K.-H., Sichel, G. Genomic localization of the human gene encoding Dr1, a negative modulator of transcription of class II and class III genes. Cytogenet. Cell Genet. 75: 186-189, 1996. [PubMed: 9040789] [Full Text: https://doi.org/10.1159/000134479]
Rozet, J.-M., Gerber, S., Perrault, I., Camuzat, A., Calvas, P., Viegas-Pequignot, E., Molina-Gomes, D., Le Paslier, D., Chumakov, I., Munnich, A., Kaplan, J. Structure and physical mapping of DR1, a TATA-binding protein-associated phosphoprotein gene, to chromosome 1p22.1 and its exclusion in Stargardt disease (STGD). Genomics 36: 554-556, 1996. [PubMed: 8884286] [Full Text: https://doi.org/10.1006/geno.1996.0508]
Wang, Y.-L., Faiola, F., Xu, M., Pan, S., Martinez, E. Human ATAC is a GCN5/PCAF-containing acetylase complex with a novel NC2-like histone fold module that interacts with the TATA-binding protein. J. Biol. Chem. 283: 33808-33815, 2008. [PubMed: 18838386] [Full Text: https://doi.org/10.1074/jbc.M806936200]
Willy, P. J., Kobayashi, R., Kadonaga, J. T. A basal transcription factor that activates or represses transcription. Science 290: 982-984, 2000. [PubMed: 11062130] [Full Text: https://doi.org/10.1126/science.290.5493.982]
Yeung, K., Kim, S., Reinberg, D. Functional dissection of a human Dr1-DRAP1 repressor complex. Molec. Cell. Biol. 17: 36-45, 1997. [PubMed: 8972183] [Full Text: https://doi.org/10.1128/MCB.17.1.36]