Alternative titles; symbols
HGNC Approved Gene Symbol: DRAP1
Cytogenetic location: 11q13.1 Genomic coordinates (GRCh38): 11:65,919,426-65,921,563 (from NCBI)
Transcriptional repression is a general mechanism for regulating transcriptional initiation in organisms ranging from yeast to humans. Accurate initiation of transcription from eukaryotic protein-encoding genes requires the assembly of a large multiprotein complex consisting of RNA polymerase II (see 180660) and general transcription factors such as TFIIA (see 600519, 600520), TFIIB (see 189963), and TFIID (see 313650). DR1 (601482) is a repressor that interacts with the TATA-binding protein (TBP; 600075) of TFIID and prevents the formation of an active transcription complex by precluding the entry of TFIIA and/or TFIIB into the preinitiation complex. The DR1-associated protein DRAP1 is a corepressor of transcription that interacts with DR1 to enhance DR1-mediated repression. The interaction between DRAP1 and DR1 is required for corepressor function and appears to stabilize the TBP-DR1-DNA complex (Mermelstein et al., 1996).
Mermelstein et al. (1996) cloned a cDNA corresponding to DRAP1 by screening HeLa cell and human liver cDNA libraries with a degenerative oligonucleotide based on the amino acid sequence of DRAP1. Two types of cDNA clones were isolated by them: a shorter cDNA, derived from the HeLa cell library, that encodes a 193-amino acid protein, and a longer cDNA, derived from the liver library, that contains a 7-amino acid insertion at residue 98. Mermelstein et al. (1996) determined that the 2 cDNA forms result from alternative splicing of the DRAP1 gene. Goppelt et al. (1996) independently cloned the DRAP1 cDNA from a human B-cell cDNA library and found that the cDNA encodes a 205-amino acid protein. The DRAP1 protein contains a histone fold motif at the N terminus and a proline-rich region at the C terminus. The binding of DRAP1 to DR1 is dependent on the histone fold motif present in each protein.
Gross (2014) mapped the DRAP1 gene to chromosome 11q13.1 based on an alignment of the DRAP1 sequence (GenBank BC010025) with the genomic sequence (GRCh38).
Mermelstein et al. (1996) showed by Northern blot analysis that DRAP1 was expressed as a 1.1-kb transcript in every tissue examined, but at higher levels in tissues containing a lower percentage of actively dividing cells. Immunohistochemical analysis of the developing rat brain demonstrated high levels of DRAP1 protein in highly differentiated, nondividing cells, but undetectable levels in actively dividing cells. Mermelstein et al. (1996) proposed that DRAP1 expression facilitates the maintenance of a differentiated state by silencing specific genes.
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.
Iratni et al. (2002) demonstrated that the transcriptional corepressor DRAP1 has a very specific role in regulation of Nodal activity during mouse embryogenesis. Iratni et al. (2002) found that loss of DRAP1 leads to severe gastrulation defects that are consistent with increased expression of Nodal and can be partially suppressed by Nodal heterozygosity. Biochemical studies indicated that DRAP1 interacts with and inhibits DNA binding by the winged-helix transcription factor FOXH1 (FAST1; 603621), a critical component of a positive feedback loop for Nodal activity. Iratni et al. (2002) proposed that DRAP1 limits the spread of a morphogenetic signal by downmodulating the response to the Nodal autoregulatory loop.
Crystal Structure
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 TFIIB.
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]
Gross, M. B. Personal Communication. Baltimore, Md. 8/29/2014.
Iratni, R., Yan, Y.-T., Chen, C., Ding, J., Zhang, Y., Price, S. M., Reinberg, D., Shen, M. M. Inhibition of excess Nodal signaling during mouse gastrulation by the transcriptional corepressor DRAP1. Science 298: 1996-1999, 2002. [PubMed: 12471260] [Full Text: https://doi.org/10.1126/science.1073405]
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]
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]
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]