Alternative titles; symbols
HGNC Approved Gene Symbol: UBR5
Cytogenetic location: 8q22.3 Genomic coordinates (GRCh38) : 8:102,252,273-102,412,700 (from NCBI)
By sequencing clones obtained from an adult brain cDNA library, Nagase et al. (1998) cloned KIAA0896. The deduced protein contains 1,230 amino acids. RT-PCR ELISA detected expression in all tissues and specific brain regions examined. Highest expression was in ovary, thalamus, and spinal cord, and lowest expression was in pancreas and spleen.
By differential display to identify progestin-induced genes expressed in breast cancer cells, followed by 5-prime RACE and screening of heart and placenta cDNA libraries, Callaghan et al. (1998) cloned EDD (E3 identified by differential display). The deduced 2,799-amino acid protein contains 2 putative nuclear localization signals, a region sharing homology with polyadenylate-binding proteins (see 604679), and a C-terminal HECT domain, which contains a conserved cysteine that binds ubiquitin via a thioester linkage. Northern blot analysis detected a 9.5-kb transcript in all tissues examined. RNA dot blot analysis found highest expression in testis, followed by brain, pituitary, and kidney. Western blot of in vitro-translated EDD detected a protein with an apparent molecular mass of 300 kD.
In addition to the domains identified by Callaghan et al. (1998) in EDD, Henderson et al. (2002) identified an N-terminal ubiquitin-associated (UBA) domain, a central UBR1 (605981)-like zinc finger motif, and a third putative nuclear localization signal.
By Northern blot analysis, Callaghan et al. (1998) demonstrated that expression of EDD was enhanced in breast cancer cells following exposure to a synthetic progestin. Inhibitors of both transcription and translation could block the induction of EDD. In vitro, EDD reversibly bound ubiquitin through a cysteine residue within the conserved C-terminal HECT domain.
Honda et al. (2002) found that HYD bound to the C-terminal BRCA1 (113705) domains of DNA topoisomerase-binding protein-1 (TOPBP1; 607760). Several ubiquitin-conjugating enzymes, UBCH4, UBCH5B (602962), and UBCH5C (602963), transferred ubiquitin molecules to HYD, leading to ubiquitination of TOPBP1. Honda et al. (2002) concluded that HYD is a ubiquitin ligase.
Henderson et al. (2002) showed that EDD interacted with importin alpha-5 (600686) through 2 consensus basic nuclear localization signals in its N terminus and was localized in cell nuclei. EDD also bound progesterone receptor (PGR; 607311) and potentiated progestin-mediated gene transactivation. The interaction with PGR did not require the LxxLL receptor-binding motif of EDD. EDD also bound calcium- and integrin-binding protein/DNA-dependent protein kinase-interacting protein (KIP; 602293), and the interaction between EDD and KIP was altered in response to DNA damage.
By analyzing several cancers of diverse tissue origin, Clancy et al. (2003) found that allelic imbalance at the EDD locus was common in several carcinomas. The EDD gene was also frequently overexpressed in breast and ovarian cancers.
Okamoto et al. (2013) addressed the molecular properties of TRF2 (602027) that are both necessary and sufficient to protect chromosome ends in mouse embryonic fibroblasts, and stated that their data supported a 2-step mechanism for TRF2-mediated end protection. First, the dimerization domain of TRF2 is required to inhibit ATM (607585) activation, the key initial step involved in the activation of a DNA damage response (DDR). Next, TRF2 independently suppresses the propagation of DNA damage signaling downstream of ATM activation. This novel modulation of the DDR at telomeres occurs at the level of the E3 ubiquitin ligase RNF168 (612688). Inhibition of RNF168 at telomeres involves the deubiquitinating enzyme BRCC3 (300617) and the ubiquitin ligase UBR5, and is sufficient to suppress chromosome end-to-end fusions. Okamoto et al. (2013) concluded that this 2-step mechanism for TRF2-mediated end protection helped to explain the apparent paradox of frequent localization of DDR proteins at functional telomeres without concurrent induction of detrimental DNA repair activities.
By FISH, Callaghan et al. (1998) mapped the EDD1 gene to chromosome 8q22.3.
Callaghan, M. J., Russell, A. J., Woollatt, E., Sutherland, G. R., Sutherland, R. L., Watts, C. K. W. Identification of a human HECT family protein with homology to the Drosophila tumor suppressor gene hyperplastic discs. Oncogene 17: 3479-3491, 1998. [PubMed: 10030672] [Full Text: https://doi.org/10.1038/sj.onc.1202249]
Clancy, J. L., Henderson, M. J., Russell, A. J., Anderson, D. W., Bova, R. J., Campbell, I. G., Choong, D. Y. H., Macdonald, G. A., Mann, G. J., Nolan, T., Brady, G., Olopade, O. I., Woollatt, E., Davies, M. J., Segara, D., Hacker, N. F., Henshall, S. M., Sutherland, R. L., Watts, C. K. W. EDD, the human orthologue of the hyperplastic discs tumour suppressor gene, is amplified and overexpressed in cancer. Oncogene 22: 5070-5081, 2003. [PubMed: 12902990] [Full Text: https://doi.org/10.1038/sj.onc.1206775]
Henderson, M. J., Russell, A. J., Hird, S., Munoz, M., Clancy, J. L., Lehrbach, G. M., Calanni, S. T., Jans, D. A., Sutherland, R. L., Watts, C. K. W. EDD, the human hyperplastic discs protein, has a role in progesterone receptor coactivation and potential involvement in DNA damage response. J. Biol. Chem. 277: 26468-26478, 2002. [PubMed: 12011095] [Full Text: https://doi.org/10.1074/jbc.M203527200]
Honda, Y., Tojo, M., Matsuzaki, K., Anan, T., Matsumoto, M., Ando, M., Saya, H., Nakao, M. Cooperation of HECT-domain ubiquitin ligase hHYD and DNA topoisomerase II-binding protein for DNA damage response. J. Biol. Chem. 277: 3599-3605, 2002. [PubMed: 11714696] [Full Text: https://doi.org/10.1074/jbc.M104347200]
Nagase, T., Ishikawa, K., Suyama, M., Kikuno, R., Hirosawa, M., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. XII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 5: 355-364, 1998. [PubMed: 10048485] [Full Text: https://doi.org/10.1093/dnares/5.6.355]
Okamoto, K., Bartocci, C., Ouzounov, I., Diedrich, J. K., Yates, J. R, III, Denchi, E. L. A two-step mechanism for TRF2-mediated chromosome-end protection. Nature 494: 502-505, 2013. [PubMed: 23389450] [Full Text: https://doi.org/10.1038/nature11873]