Alternative titles; symbols
HGNC Approved Gene Symbol: UBR2
Cytogenetic location: 6p21.1 Genomic coordinates (GRCh38) : 6:42,564,029-42,693,505 (from NCBI)
Proteolysis by the ubiquitin-proteasome system controls the concentration of many regulatory proteins. The selectivity of ubiquitylation is determined by ubiquitin E3 ligases, which recognize the substrate's destabilization signal, or degron. The E3 ligase UBR2 participates in the N-end rule pathway, which targets proteins bearing an N-terminal degron, or N-degron (Kwon et al., 2003).
By sequencing clones obtained from a size-fractionated brain cDNA library, Nagase et al. (1997) cloned UBR2, which they designated KIAA0349. The deduced 1,275-amino acid protein shares 19.9% identity over 710 amino acids with an S. cerevisiae N-end-recognizing protein. RT-PCR of several tissues detected UBR2 expression only in testis.
Kwon et al. (2003) cloned mouse Ubr2. The deduced protein has a calculated molecular mass of about 200 kD.
Kwon et al. (2003) determined that the mouse Ubr2 gene contains 48 exons and spans about 98 kb.
By radiation hybrid analysis, Nagase et al. (1997) mapped the UBR2 gene to chromosome 6. Using radiation hybrid analysis and FISH, Kwon et al. (2003) mapped the UBR2 gene to chromosome 6p21-p11 and the mouse Ubr2 gene to the middle of chromosome 17.
Kwon et al. (2003) determined that mouse Ubr2 bound to type-1 (arg) and type-2 (leu or phe) destabilizing N-terminal residues of a test substrate or a 12-residue peptide. It did not bind to stabilizing (met or gly), secondary destabilizing (asp), or type-3 destabilizing (ser, thr, or ala) residues.
Using antibodies to human RECQL4 (603780), Yin et al. (2004) found that the bulk of RECQL4 was present in the cytoplasmic extract of HeLa cells. RECQL4 from HeLa cells was isolated as a stable complex with UBR1 (605981) and UBR2, which are ubiquitin ligases of the N-end rule pathway. Although UBR1 and UBR2 mediate polyubiquitylation (and subsequent degradation) of their substrates, the UBR1/2-bound RECQL4 was not ubiquitylated in vivo and was a long-lived protein in HeLa cells. Yin et al. (2004) showed that the isolated RECQL4-UBR1/2 complex had a DNA-stimulated ATPase activity but was inactive in DNA-based assays for helicases and translocases.
Using immunohistochemical analysis, An et al. (2010) showed that Ubr2 localized to meiotic chromatin regions in mouse spermatocytes, including unsynapsed axes linked to transcriptional silencing, and marked meiotic sex chromosome inactivation (MSCI). Ubr2 mediated monoubiquitination and polyubiquitination of histone H2a (see 613499) by binding to Hr6b (UBE2B; 179095) and H2a, enhancing interaction of Hr6b with H2a, and facilitating transfer of ubiquitin from Hr6b to H2a. Chromosomewide ubiquitination of H2a was disrupted in Ubr2 -/- spermatocytes, causing defects in transcriptional silencing of genes linked to unsynapsed axes of sex chromosomes in meiosis due to insufficiency in histone ubiquitination and failure to exclude proteins involved in transcription from chromatin. The localization pattern of Ubr2 to unsynapsed axial regions of autosomes was distinct from that of Brca1 (113705), a protein also involved in meiotic chromatin inactivation, and Ubr2-dependent histone ubiquitination was not essential for the Brca1-dependent histone phosphorylation pathway during MSCI.
Using yeast 2-hybrid assays, Oh et al. (2020) showed that 5 human enzymes of the arg/N-degron pathway formed a targeting complex: NTAQ1 (620846), NTAN1 (615367), ATE1 (607103), UBR1, and UBR2. In the complex, NTAN1 bound to NTAQ1, ATE1, and UBR1/UBR2. NTAQ1 and ATE1 also interacted with UBR1/UBR2. In addition, NTAQ1 self-interacted to form homodimers. Formation of an analogous targeting complex was observed in yeast. The presence of a multienzyme targeting complex of the arg/N-degron pathway appeared to support the concept of superchanneling, in which enzymes or assemblies of enzymes that catalyze sequential reactions exhibit substrate channeling, where a reaction intermediate can be transferred between active sites of interacting enzymes without release of intermediate to the bulk solution.
Kwon et al. (2003) found that Ubr2 knockout in mice was embryonic lethal depending on both the gender and genetic background. In an inbred strain, the Ubr2 -/- genotype was lethal to most embryos of either gender. In a mixed background, most Ubr2 -/- females died as embryos and Ubr2 -/- males were viable but infertile due to postnatal degeneration of the testes. The gross architecture of Ubr2 -/- testes was normal and spermatogonia were intact, but spermatocytes were arrested between leptotene/zygotene and pachytene, and died through apoptosis. A conspicuous defect of Ubr2 -/- spermatocytes was the absence of intact synaptonemal complexes. Ubr2 +/- heterozygotes were produced at approximately mendelian frequency and were phenotypically normal except for reduced fertility compared with wildtype mice.
An, J. Y., Kim, E.-A., Jiang, Y., Zakrzewska, A., Kim, D. E., Lee, M. J., Mook-Jung, I., Zhang, Y., Kwon, Y. T. UBR2 mediates transcriptional silencing during spermatogenesis via histone ubiquitination. Proc. Nat. Acad. Sci. 107: 1912-1917, 2010. [PubMed: 20080676] [Full Text: https://doi.org/10.1073/pnas.0910267107]
Kwon, Y. T., Xia, Z., An, J. Y., Tasaki, T., Davydov, I. V., Seo, J. W., Sheng, J., Xie, Y., Varshavsky, A. Female lethality and apoptosis of spermatocytes in mice lacking the UBR2 ubiquitin ligase of the N-end rule pathway. Molec. Cell. Biol. 23: 8255-8271, 2003. [PubMed: 14585983] [Full Text: https://doi.org/10.1128/MCB.23.22.8255-8271.2003]
Nagase, T., Ishikawa, K., Nakajima, D., Ohira, M., Seki, N., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., Ohara, O. Prediction of the coding sequences of unidentified human genes. VII. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. DNA Res. 4: 141-150, 1997. [PubMed: 9205841] [Full Text: https://doi.org/10.1093/dnares/4.2.141]
Oh, J. H., Hyun, J. Y., Chen, S. J., Varshavsky, A. Five enzymes of the Arg/N-degron pathway form a targeting complex: The concept of superchanneling. Proc. Nat. Acad. Sci. 117: 10778-10788, 2020. [PubMed: 32366662] [Full Text: https://doi.org/10.1073/pnas.2003043117]
Yin, J., Kwon, Y. T., Varshavsky, A., Wang, W. RECQL4, mutated in the Rothmund-Thomson and RAPADILINO syndromes, interacts with ubiquitin ligases UBR1 and UBR2 of the N-end rule pathway. Hum. Molec. Genet. 13: 2421-2430, 2004. [PubMed: 15317757] [Full Text: https://doi.org/10.1093/hmg/ddh269]