Ubiquitin-conjugating E2 enzyme variant proteins constitute a distinct subfamily within the E2 protein family. They have sequence similarity to other ubiquitin-conjugating enzymes, but they don't have the conserved cysteine residue critical for their catalytic activity. Therefore they codify for inactive proteins. In humans, there are two different UBE2V proteins encoded by separate genes, UBE2V1 and UBE2V2. They are located in different chromosomes, while UEV1 is in Chr 20, UEV2 is in Chr 8. UEV1 located in Chr 20 is the one that can be co-expressed with the upstream gene Kua generating a diferent ubiquitin-conjugating enzime variant.
Alternative names: CROC-1, UEV1, UEV1A, UBE2V
The gene UBE2V1 is located in chromosome 20 (20q13.2), in strand minus. It has a genomic size of 34832bp (chr20:48131070-48165901 in UCSC Genome Browser).
Fig.1The gene UBE2V1 is located in Chr 20 q13.2
The gene UBE2V1 has 5 exons, which depending on the transcript and isoform are or not translated into protein. We can find different numbers of transcripts for this gene depending on the database that we use. According to Ensembl there are 5 transcript variants for this gene:
Transcript variant 1:
Transcript variant 2:
Transcripts 1 and 2 give rise to the same protein isoform.
Transcript variant 3:
Transcript variant 4:
Transcript variant 5:
So, gene UBE2V1 would give rise to 4 protein isoforms, with two similar transcripts encoding for the same isoform and each of the other three transcripts for a different isoform.
Diferent transcripts containing different exons are a result of alternative splicing. In all the cases of alternative splicing for this gene the reading frame is mantained, since the resulting protein has the same aminoacid sequence in all the isoforms.
List of the predicted orthologue genes in other species from ENSEMBL:
| IMAGE | SPECIE | ENSEMBL ID | TARGET % ID |
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P. troglodytes | ENSPTRG00000013615 | 99% |
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M. mulatta | ENSMMUG00000012228 | 98% |
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B. taurus | ENSBTAG00000027316 | 96% |
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X. tropicalis | ENSXETG00000027365 | 95% |
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F. catus | ENSFCAG00000010559 | 93% |
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D. novemcinctus | ENSDNOG00000013756 | 92% |
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D. rerio | ENSDARG00000041875 | 86% |
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E. europaeus | ENSEEUG00000002785 | 84% |
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T. belangeri | ENSTBEG00000008732 | 81% |
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M. domestica | ENSMODG00000016312 | 79% |
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G. gallus | ENSGALG00000008015 | 78% |
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O. latipes | ENSORLG00000015058 | 72% |
There is a high level of conservation between the different orthologues in the different species. The percentage of homology descends the more philogenetically separated the species are.
Furthermore, a phylogenetic tree was made with the protein sequence (from NCBI) of six different species using the program CLUSTALW. The tree obtained shows the correct phylogeny relationship among species. This means the protein has been conserved throughout evolution, due to the selective pressure to mantain the functionality.
In order to characterize the gene expression in human cell types and tissues, some miroarray chips from UCSC Genome Browser have been analyzed. The figures show the ratios of two of these experiments, where red colour indicates the gene is highly expressed in the tissue and green that it is underexpressed.
Normal Human Tissue cDNA Microarrays
GNF Expression Atlas 2 Data from U133A and GNF1H Chips
UBE2V1 is highly expressed in:
Besides we searched the VisiGene Image Browser to find in situ images of UBE2V1 expression. We found an image of a male mouse brain (Stage: 5.3 week old pup)
Fig.3 Visigene male mouse brain image.
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UEV proteins are enzymatically inactive variants of the E2 ubiquitin-conjugating enzymes, lacking a cysteine residue in their catalytic centre that is critical for the activity of E2s.The protein encoded by this gene is located in the nucleus and regulates noncanonical elongation of ubiquitin chains, a variant of polyubiquitination.
In Saccharomyces cerevisiae, UEV protein Mms2 interacts with the E2 enzyme Ubc13p, and the resulting heterodimer is competent for the elongation of polyubiquitin chains. In the resulting polyubiquitin chains, Lys 63, instead of the canonical Lys 48, is used for the Gly–Lys isopeptide bonds between ubiquitin moieties. Modification of proteins by this variant polyubiquitin chain may be reversible, and could modulate the function of target proteins, without directing them for degradation.
In yeast S. cerevisiae, UEV is part of a DNA repair pathway. It has therefore a role in the protection of cells from DNA damaging agents.
In mammalian cells, UEV proteins can modulate c-FOS transcription and the G2-M transition of the cell cycle. Overexpression of UEV1 in human colon cancer cells induces the accumulation of cells in G2-M and poliploidy, apoptosis, and inhibition of cell differentiation.
The characterizations of the gene's promoter region and the transcription factors that are likely to bind to it has been done by two ways: with the program PROMO and with a PERL program developed by ourselves.
1.Perl program:
The folowing items are needed:
- The promoter sequence of the gene UBE2V1
- Document TFs matrices, which contains 13 selected TFs matrices
- Perl program PERL PROGRAM(identificacio_de_lufs.pl), which has been developed by the authors.
The program has to be executed in Linux terminal by typing:
$ ./identificacio_de_lufs.pl humanfactors_selectedmatrices.txt sequenciapromotora_UBE.fa After running the program several times we show the obtained results in the following table, where the position in the promoter region the TF binds to and the score and p-value are noted:| Transcription factor | Position | Score | p-value |
| AP-1 | 607-613 | 5.34044 | 0.52 |
| AR | 907-913 | 6.76042 | 0.06 |
| c-Myc | 775-780 | 8.47617 | 0.14 |
| NF-AT1 | 510-516 | 4.86609 | 0.52 |
| NF-kappaB | 875-883 | 6.10399 | 0.43 |
| SRF | 64-72 | 1.40820 | 0.19 |
| YY1 | 891-896 | 5.23748 | 0.87 |
| RXR-alpha | 643-648 | 7.23767 | 0.27 |
| HIF-1 | 57-65 | 1.56189 | 0.59 |
| AhR | 115-121 | 7.17135 | 0.17 |
| PU.1 | 870-876 | 7.62815 | 0.11 |
| HNF-4 | 59-66 | 1.58026 | 0.53 |
| NRSF | 55-63 | 1.46653 | 0.25 |
We have reduced the list of TFs provided by PROMO by selecting the ones with smaller RE-equally values (using a 0,1 cutoff). RE-equally gives the number of expected occurrences of the match in a random sequence of the same length as the query sequence according to the dissimilarity index (15%) consifering equiprobability for the 4 nucleotides.
We can compare the results obtained with the two different methods, bearing in mind however that the program is just a very simple approach to the problem, and hence has a limited predictability.
The coincident TFs are the following: NF-AT1, NF-kappaB, YY1, RXR-alpha, AhR and HNF-4.