Alternative titles; symbols
HGNC Approved Gene Symbol: URI1
Cytogenetic location: 19q12 Genomic coordinates (GRCh38) : 19:29,923,657-30,016,612 (from NCBI)
By micropeptide sequence analysis, PCR with degenerate primers, and screening of a liver cDNA library, Van Leuven et al. (1998) isolated a cDNA encoding NNX3. The deduced 458-amino acid protein is 75% identical to the mouse protein. It contains 7 cysteines, 3 of which are positionally conserved with mouse, an acidic region, and a nuclear localization signal, as well as potential glycosylation, myristoylation, and phosphorylation sites. NNX3 lacks a signal peptide and a transmembrane domain. Western blot analysis showed expression of an approximately 65-kD protein, higher than the predicted 50 kD. Immunofluorescence microscopy demonstrated predominantly cytoplasmic expression. Northern blot analysis revealed wide expression of a 2.6-kb transcript that was most abundant in skeletal muscle. Immunohistochemical analysis indicated strong expression in mouse embryonic brain and neuronal tissue, as well as expression in numerous other tissues paralleling expression observed in human autopsy specimens. Expression was also detected in small cell lung carcinoma cells and Reed-Sternberg cells of Hodgkin disease (236000), although expression was not found in all tumor cell lines.
Independently, Dorjsuren et al. (1998) cloned and characterized what they termed RMP.
Using genomic sequence analysis, Van Leuven et al. (1998) determined that the human and mouse NNX3 genes contain 9 exons.
Using genomic sequence analysis and FISH, Van Leuven et al. (1998) mapped the NNX3 gene to chromosome 19q12.
Gstaiger et al. (2003) found that RMP, which they called URI for 'unconventional prefoldin RPB5 interactor,' exists in a 1-megadalton multiprotein complex in human cells. It appears to occupy an essential role therein as a scaffolding protein able to assemble, through its prefoldin (PFD) homology and RPB5-binding domains, a prefoldin-like complex that contains other PFDs and proteins with roles in transcription and ubiquitination. The URI complex includes PFD2; a PFD4-related protein; RPB5 (180664), a subunit shared by all 3 RNA polymerases (pols); the adenosine triphosphatases TIP48 (604788) and TIP49 (603449); and URI. Gstaiger et al. (2003) noted that a published cDNA encoding URI was rearranged at the N terminus. The corrected cDNA sequence encodes a protein of 534 amino acids with an alpha-class PFD homology domain at its N terminus. Functional analysis of the yeast and human orthologs of URI revealed that both are targets of nutrient signaling and participate in gene expression controlled by the TOR kinase (601231). Gstaiger et al. (2003) created HeLa cells that had been stably silenced for URI expression by small interfering RNA (siRNA) and compared their transcriptional profiles in response to rapamycin. After treatment of control cells for 2 hours with rapamycin, the expression of 194 genes was changed. Of these 194, 28 genes, whose products are primarily involved in the regulation of cell growth and maintenance and cell communication, had transcription patterns that were significantly altered in URI-silenced HeLa cells. Gstaiger et al. (2003) concluded that this suggested a functional link between the presence of URI and the implementation of a proper rapamycin-sensitive transcription response in human cells.
Chaves-Perez et al. (2019) showed that high-dose irradiation increases URI levels in mouse intestinal crypt, but organ regeneration correlates with URI reductions. URI overexpression in intestine protected mice from radiation-induced gastrointestinal syndrome (GIS), whereas halving URI expression sensitized mice to ionizing radiation. URI specifically inhibited beta-catenin (116806) in stem cell-like label-retaining (LR) cells, which are essential for organ regeneration after ionizing radiation. URI reduction activates beta-catenin-induced c-MYC (190080) proliferation of and DNA damage to LR cells, rendering them radiosensitive. Chaves-Perez et al. (2019) concluded that URI labels LR cells which promote tissue regeneration in response to high-dose irradiation, and c-MYC inhibitors could be countermeasures for humans at risk of developing GIS.
Chaves-Perez, A., Yilmaz, M., Perna, C., de la Rosa, S., Djouder, N. URI is required to maintain intestinal architecture during ionizing radiation. Science 364: eaaq1165, 2019. Note: Electronic Article. [PubMed: 31147493] [Full Text: https://doi.org/10.1126/science.aaq1165]
Dorjsuren, D., Lin, Y., Wei, W., Yamashita, T., Nomura, T., Hayashi, N., Murakami, S. RMP, a novel RNA polymerase II subunit 5-interacting protein, counteracts transactivation by hepatitis B virus X protein. Molec. Cell Biol. 18: 7546-7555, 1998. [PubMed: 9819440] [Full Text: https://doi.org/10.1128/MCB.18.12.7546]
Gstaiger, M., Luke, B., Hess, D., Oakeley, E. J., Wirbelauer, C., Blondel, M., Vigneron, M., Peter, M., Krek, W. Control of nutrient-sensitive transcription programs by the unconventional prefoldin URI. Science 302: 1208-1212, 2003. [PubMed: 14615539] [Full Text: https://doi.org/10.1126/science.1088401]
Van Leuven, F., Torrekens, S., Moechars, D., Hilliker, C., Buellens, M., Bollen, M., Delabie, J. Molecular cloning of a gene on chromosome 19q12 coding for a novel intracellular protein: analysis of expression in human and mouse tissues and in human tumor cells, particularly Reed-Sternberg cells in Hodgkin disease. Genomics 54: 511-520, 1998. [PubMed: 9878255] [Full Text: https://doi.org/10.1006/geno.1998.5609]