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Fusion Protein:RARA-CDK12 |
Fusion Gene and Fusion Protein Summary |
 Fusion gene summary |
| Fusion partner gene information | Fusion gene name: RARA-CDK12 | FusionPDB ID: 72286 | FusionGDB2.0 ID: 72286 | Hgene | Tgene | Gene symbol | RARA | CDK12 | Gene ID | 5914 | 51755 |
| Gene name | retinoic acid receptor alpha | cyclin dependent kinase 12 | |
| Synonyms | NR1B1|RAR | CRK7|CRKR|CRKRS | |
| Cytomap | 17q21.2 | 17q12 | |
| Type of gene | protein-coding | protein-coding | |
| Description | retinoic acid receptor alphaRAR-alphanuclear receptor subfamily 1 group B member 1nucleophosmin-retinoic acid receptor alpha fusion protein NPM-RAR long formretinoic acid nuclear receptor alpha variant 1retinoic acid nuclear receptor alpha variant 2 | cyclin-dependent kinase 12CDC2-related protein kinase 7Cdc2-related kinase, arginine/serine-richcell division cycle 2-related protein kinase 7cell division protein kinase 12 | |
| Modification date | 20200327 | 20200313 | |
| UniProtAcc | P10276 Main function of 5'-partner protein: FUNCTION: Receptor for retinoic acid (PubMed:19850744, PubMed:16417524, PubMed:20215566). Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes (PubMed:28167758). The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5 (PubMed:28167758, PubMed:19398580). In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone deacetylation, chromatin condensation and transcriptional suppression (PubMed:16417524). On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation (PubMed:9267036, PubMed:19850744, PubMed:20215566). Formation of a complex with histone deacetylases might lead to inhibition of RARE DNA element binding and to transcriptional repression (PubMed:28167758). Transcriptional activation and RARE DNA element binding might be supported by the transcription factor KLF2 (PubMed:28167758). RARA plays an essential role in the regulation of retinoic acid-induced germ cell development during spermatogenesis (By similarity). Has a role in the survival of early spermatocytes at the beginning prophase of meiosis (By similarity). In Sertoli cells, may promote the survival and development of early meiotic prophase spermatocytes (By similarity). In concert with RARG, required for skeletal growth, matrix homeostasis and growth plate function (By similarity). Together with RXRA, positively regulates microRNA-10a expression, thereby inhibiting the GATA6/VCAM1 signaling response to pulsatile shear stress in vascular endothelial cells (PubMed:28167758). In association with HDAC3, HDAC5 and HDAC7 corepressors, plays a role in the repression of microRNA-10a and thereby promotes the inflammatory response (PubMed:28167758). {ECO:0000250|UniProtKB:P11416, ECO:0000269|PubMed:16417524, ECO:0000269|PubMed:19398580, ECO:0000269|PubMed:19850744, ECO:0000269|PubMed:20215566, ECO:0000269|PubMed:28167758, ECO:0000269|PubMed:9267036}. | Q9NYV4 Main function of 5'-partner protein: FUNCTION: Cyclin-dependent kinase that phosphorylates the C-terminal domain (CTD) of the large subunit of RNA polymerase II (POLR2A), thereby acting as a key regulator of transcription elongation. Regulates the expression of genes involved in DNA repair and is required for the maintenance of genomic stability. Preferentially phosphorylates 'Ser-5' in CTD repeats that are already phosphorylated at 'Ser-7', but can also phosphorylate 'Ser-2'. Required for RNA splicing, possibly by phosphorylating SRSF1/SF2. Involved in regulation of MAP kinase activity, possibly leading to affect the response to estrogen inhibitors. {ECO:0000269|PubMed:11683387, ECO:0000269|PubMed:19651820, ECO:0000269|PubMed:20952539, ECO:0000269|PubMed:22012619, ECO:0000269|PubMed:24662513}. | |
| Ensembl transtripts involved in fusion gene | ENST ids | ENST00000254066, ENST00000394081, ENST00000394086, ENST00000394089, ENST00000425707, ENST00000420042, | ENST00000430627, ENST00000447079, ENST00000559545, |
| Fusion gene scores for assessment (based on all fusion genes of FusionGDB 2.0) | * DoF score | 47 X 22 X 8=8272 | 36 X 30 X 14=15120 |
| # samples | 74 | 55 | |
| ** MAII score | log2(74/8272*10)=-3.48263900979862 possibly effective Gene in Pan-Cancer Fusion Genes (peGinPCFGs). DoF>8 and MAII<0 | log2(55/15120*10)=-4.78088271069641 possibly effective Gene in Pan-Cancer Fusion Genes (peGinPCFGs). DoF>8 and MAII<0 | |
| Fusion gene context | PubMed: RARA [Title/Abstract] AND CDK12 [Title/Abstract] AND fusion [Title/Abstract] | ||
| Fusion neoantigen context | PubMed: RARA [Title/Abstract] AND CDK12 [Title/Abstract] AND neoantigen [Title/Abstract] | ||
| Most frequent breakpoint (based on all fusion genes of FusionGDB 2.0) | RARA(38474700)-CDK12(37646810), # samples:3 RARA(38504716)-CDK12(37686857), # samples:3 RARA(38504716)-CDK12(37686856), # samples:3 | ||
| Anticipated loss of major functional domain due to fusion event. | RARA-CDK12 seems lost the major protein functional domain in Hgene partner, which is a CGC by not retaining the major functional domain in the partially deleted in-frame ORF. RARA-CDK12 seems lost the major protein functional domain in Hgene partner, which is a CGC by not retaining the major functional domain in the partially deleted in-frame ORF. RARA-CDK12 seems lost the major protein functional domain in Hgene partner, which is a essential gene by not retaining the major functional domain in the partially deleted in-frame ORF. RARA-CDK12 seems lost the major protein functional domain in Hgene partner, which is a essential gene by not retaining the major functional domain in the partially deleted in-frame ORF. RARA-CDK12 seems lost the major protein functional domain in Hgene partner, which is a CGC due to the frame-shifted ORF. RARA-CDK12 seems lost the major protein functional domain in Hgene partner, which is a epigenetic factor due to the frame-shifted ORF. RARA-CDK12 seems lost the major protein functional domain in Hgene partner, which is a IUPHAR drug target due to the frame-shifted ORF. RARA-CDK12 seems lost the major protein functional domain in Hgene partner, which is a transcription factor due to the frame-shifted ORF. RARA-CDK12 seems lost the major protein functional domain in Tgene partner, which is a CGC due to the frame-shifted ORF. RARA-CDK12 seems lost the major protein functional domain in Tgene partner, which is a essential gene due to the frame-shifted ORF. RARA-CDK12 seems lost the major protein functional domain in Tgene partner, which is a IUPHAR drug target due to the frame-shifted ORF. RARA-CDK12 seems lost the major protein functional domain in Tgene partner, which is a kinase due to the frame-shifted ORF. | ||
| * DoF score (Degree of Frequency) = # partners X # break points X # cancer types ** MAII score (Major Active Isofusion Index) = log2(# samples/DoF score*10) |
| Gene ontology of each fusion partner gene with evidence of Inferred from Direct Assay (IDA) from Entrez |
| Partner | Gene | GO ID | GO term | PubMed ID |
| Hgene | RARA | GO:0007165 | signal transduction | 2825025 |
| Hgene | RARA | GO:0030853 | negative regulation of granulocyte differentiation | 19917671 |
| Hgene | RARA | GO:0032689 | negative regulation of interferon-gamma production | 18416830 |
| Hgene | RARA | GO:0032720 | negative regulation of tumor necrosis factor production | 18416830 |
| Hgene | RARA | GO:0032736 | positive regulation of interleukin-13 production | 18416830 |
| Hgene | RARA | GO:0032753 | positive regulation of interleukin-4 production | 18416830 |
| Hgene | RARA | GO:0032754 | positive regulation of interleukin-5 production | 18416830 |
| Hgene | RARA | GO:0045630 | positive regulation of T-helper 2 cell differentiation | 18416830 |
| Hgene | RARA | GO:0045892 | negative regulation of transcription, DNA-templated | 20080953 |
| Hgene | RARA | GO:0045893 | positive regulation of transcription, DNA-templated | 18845237|19850744|20080953 |
| Hgene | RARA | GO:0045944 | positive regulation of transcription by RNA polymerase II | 19850744|21131358 |
| Hgene | RARA | GO:0071300 | cellular response to retinoic acid | 19917671 |
| Hgene | RARA | GO:0071391 | cellular response to estrogen stimulus | 20080953 |
| Tgene | CDK12 | GO:0046777 | protein autophosphorylation | 11683387 |
| Four levels of functional features of fusion genes Go to FGviewer search page for the most frequent breakpoint (https://ccsmweb.uth.edu/FGviewer/chr17:38474700/chr17:37646810) - FGviewer provides the online visualization of the retention search of the protein functional features across DNA, RNA, protein, and pathological levels. - How to search 1. Put your fusion gene symbol. 2. Press the tab key until there will be shown the breakpoint information filled. 4. Go down and press 'Search' tab twice. 4. Go down to have the hyperlink of the search result. 5. Click the hyperlink. 6. See the FGviewer result for your fusion gene. |
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| Retention analysis results of each fusion partner protein across 39 protein features of UniProt such as six molecule processing features, 13 region features, four site features, six amino acid modification features, two natural variation features, five experimental info features, and 3 secondary structure features, are available here. |
| Fusion gene breakpoints across RARA (5'-gene) * Click on the image to open the UCSC genome browser with custom track showing this image in a new window. |
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| Fusion gene breakpoints across CDK12 (3'-gene) * Click on the image to open the UCSC genome browser with custom track showing this image in a new window. |
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Fusion Amino Acid Sequences |
| Fusion information from ORFfinder translation from full-length transcript sequence from FusionPDB. |
| Henst | Tenst | Hgene | Hchr | Hbp | Hstrand | Tgene | Tchr | Tbp | Tstrand | Seq length (transcript) | BP loci (transcript) | Predicted start (transcript) | Predicted stop (transcript) | Seq length (amino acids) |
| ENST00000254066 | RARA | chr17 | 38504716 | + | ENST00000430627 | CDK12 | chr17 | 37686883 | + | 2629 | 782 | 775 | 1467 | 230 |
| ENST00000394089 | RARA | chr17 | 38504716 | + | ENST00000430627 | CDK12 | chr17 | 37686883 | + | 2704 | 857 | 850 | 1542 | 230 |
| ENST00000394086 | RARA | chr17 | 38504716 | + | ENST00000430627 | CDK12 | chr17 | 37686883 | + | 2224 | 377 | 370 | 1062 | 230 |
| ENST00000394081 | RARA | chr17 | 38504716 | + | ENST00000430627 | CDK12 | chr17 | 37686883 | + | 2501 | 654 | 647 | 1339 | 230 |
| ENST00000254066 | RARA | chr17 | 38504716 | + | ENST00000430627 | CDK12 | chr17 | 37686884 | + | 2629 | 782 | 775 | 1467 | 230 |
| ENST00000394089 | RARA | chr17 | 38504716 | + | ENST00000430627 | CDK12 | chr17 | 37686884 | + | 2704 | 857 | 850 | 1542 | 230 |
| ENST00000394086 | RARA | chr17 | 38504716 | + | ENST00000430627 | CDK12 | chr17 | 37686884 | + | 2224 | 377 | 370 | 1062 | 230 |
| ENST00000394081 | RARA | chr17 | 38504716 | + | ENST00000430627 | CDK12 | chr17 | 37686884 | + | 2501 | 654 | 647 | 1339 | 230 |
| DeepORF prediction of the coding potential based on the fusion transcript sequence of in-frame fusion genes. DeepORF is a coding potential classifier based on convolutional neural network by comparing the real Ribo-seq data. If the no-coding score < 0.5 and coding score > 0.5, then the in-frame fusion transcript is predicted as being likely translated. |
| Henst | Tenst | Hgene | Hchr | Hbp | Hstrand | Tgene | Tchr | Tbp | Tstrand | No-coding score | Coding score |
| ENST00000254066 | ENST00000430627 | RARA | chr17 | 38504716 | + | CDK12 | chr17 | 37686883 | + | 0.20875348 | 0.79124653 |
| ENST00000394089 | ENST00000430627 | RARA | chr17 | 38504716 | + | CDK12 | chr17 | 37686883 | + | 0.18178359 | 0.8182164 |
| ENST00000394086 | ENST00000430627 | RARA | chr17 | 38504716 | + | CDK12 | chr17 | 37686883 | + | 0.20541008 | 0.7945899 |
| ENST00000394081 | ENST00000430627 | RARA | chr17 | 38504716 | + | CDK12 | chr17 | 37686883 | + | 0.25347763 | 0.7465223 |
| ENST00000254066 | ENST00000430627 | RARA | chr17 | 38504716 | + | CDK12 | chr17 | 37686884 | + | 0.20875348 | 0.79124653 |
| ENST00000394089 | ENST00000430627 | RARA | chr17 | 38504716 | + | CDK12 | chr17 | 37686884 | + | 0.18178359 | 0.8182164 |
| ENST00000394086 | ENST00000430627 | RARA | chr17 | 38504716 | + | CDK12 | chr17 | 37686884 | + | 0.20541008 | 0.7945899 |
| ENST00000394081 | ENST00000430627 | RARA | chr17 | 38504716 | + | CDK12 | chr17 | 37686884 | + | 0.25347763 | 0.7465223 |
| Predicted full-length fusion amino acid sequences. For individual full-length fusion transcript sequence from FusionPDB, we ran ORFfinder and chose the longest ORF among all the predicted ones. |
Get the fusion protein sequences from here. |
| Fusion protein sequence information is available in the fasta format. >FusionGDB ID_FusionGDB isoform ID_FGname_Hgene_Hchr_Hbp_Henst_Tgene_Tchr_Tbp_Tenst_length(fusion AA) seq_BP |
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Fusion Protein Breakpoint Sequences for RARA-CDK12 |
| +/-13 AA sequence from the breakpoints of the fusion protein sequences. |
| Hgene | Hchr | Hbp | Tgene | Tchr | Tbp | Length(fusion protein) | BP in fusion protein | Peptide |
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Potential FusionNeoAntigen Information of RARA-CDK12 in HLA I |
| Multiple sequence alignments of the potential FusionNeoAntigens per fusion breakpoints. If the MSA is empty, then it means that there were predicted fusion neoantigens in this fusion breakpoint, but those predicted fusion neoantigens were not across the breakpoint, which is not fusion-specific. |
| Potential FusionNeoAntigen Information * We used NetMHCpan v4.1 (%rank<0.5) and deepHLApan v1.1 (immunogenic score>0.5) |
| Fusion gene | Hchr | Hbp | Tgene | Tchr | Tbp | HLA I | FusionNeoAntigen peptide | Binding score | Immunogenic score | Neoantigen start (at BP 13) | Neoantigen end (at BP 13) |
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Potential FusionNeoAntigen Information of RARA-CDK12 in HLA II |
| Multiple sequence alignments of the potential FusionNeoAntigens per fusion breakpoints. If the MSA is empty, then it means that there were predicted fusion neoantigens in this fusion breakpoint, but those predicted fusion neoantigens were not across the breakpoint, which is not fusion-specific. |
| Potential FusionNeoAntigen Information * We used NetMHCIIpan v4.1 (%rank<0.5). |
| Fusion gene | Hchr | Hbp | Tgene | Tchr | Tbp | HLA II | FusionNeoAntigen peptide | Neoantigen start (at BP 13) | Neoantigen end (at BP 13) |
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Fusion breakpoint peptide structures of RARA-CDK12 |
| 3D structures of the fusion breakpoint peptide of 14AA sequence that have potential fusion neoantigens * The minimum length of the amino acid sequence in RoseTTAFold is 14AA. Here, we predicted the 14AA fusion protein breakpoint sequence not the fusion neoantigen peptide, which is shorter than 14 AA. |
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Filtering FusionNeoAntigens Through Checking the Interaction with HLAs in 3D of RARA-CDK12 |
| Virtual screening between 25 HLAs (from PDB) and FusionNeoAntigens * We used Glide to predict the interaction between HLAs and neoantigens. |
| HLA allele | PDB ID | File name | BPseq | Docking score | Glide score |
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Vaccine Design for the FusionNeoAntigens of RARA-CDK12 |
| mRNA and peptide sequences of FusionNeoAntigens that have potential interaction with HLA-Is. |
| Fusion gene | Hchr | Hbp | Tchr | Tbp | Start in +/-13AA | End in +/-13AA | FusionNeoAntigen peptide sequence | FusionNeoAntigen RNA sequence |
| mRNA and peptide sequences of FusionNeoAntigens that have potential interaction with HLA-IIs. |
| Fusion gene | Hchr | Hbp | Tchr | Tbp | Start in +/-13AA | End in +/-13AA | FusionNeoAntigen peptide | FusionNEoAntigen RNA sequence |
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Information of the samples that have these potential fusion neoantigens of RARA-CDK12 |
| These samples were reported as having these fusion breakpoints. For individual breakpoints, we checked the open reading frames considering multiple gene isoforms and chose the in-frame fusion genes only. Then, we made fusion protein sequences and predicted the fusion neoantigens. These fusion-positive samples may have these potential fusion neoantigens. |
| Cancer type | Fusion gene | Hchr | Hbp | Henst | Tchr | Tbp | Tenst | Sample |
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Potential target of CAR-T therapy development for RARA-CDK12 |
| Predicted 3D structure. We used RoseTTAFold. |
| Retention analysis result of each fusion partner protein across 39 protein features of UniProt such as six molecule processing features, 13 region features, four site features, six amino acid modification features, two natural variation features, five experimental info features, and 3 secondary structure features. Here, to provide the retention of the transmembrane domain, we only show the protein feature retention information of those transmembrane features * Minus value of BPloci means that the break point is located before the CDS. |
| - In-frame and retained 'Transmembrane'. |
| Partner | Gene | Hbp | Tbp | ENST | Strand | BPexon | TotalExon | Protein feature loci | *BPloci | TotalLen | Protein feature | Protein feature note |
| Subcellular localization prediction of the transmembrane domain retained fusion proteins * We used DeepLoc 1.0. The order of the X-axis of the barplot is as follows: Entry_ID, Localization, Type, Nucleus, Cytoplasm, Extracellular, Mitochondrion, Cell_membrane, Endoplasmic_reticulum, Plastid, Golgi.apparatus, Lysosome.Vacuole, Peroxisome. Y-axis is the output score of DeepLoc. Clicking the image will open a new tab with a large image. |
| Hgene | Hchr | Hbp | Henst | Tgene | Tchr | Tbp | Tenst | DeepLoc result |
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Related Drugs to RARA-CDK12 |
| Drugs used for this fusion-positive patient. (Manual curation of PubMed, 04-30-2022 + MyCancerGenome) |
| Hgene | Tgene | Drug | Source | PMID |
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Related Diseases to RARA-CDK12 |
| Diseases that have this fusion gene. (Manual curation of PubMed, 04-30-2022 + MyCancerGenome) |
| Hgene | Tgene | Disease | Source | PMID |
| Diseases associated with fusion partners. (DisGeNet 4.0) |
| Partner | Gene | Disease ID | Disease name | # pubmeds | Source |
| Hgene | RARA | C0023487 | Acute Promyelocytic Leukemia | 24 | CTD_human;ORPHANET |
| Hgene | RARA | C0036341 | Schizophrenia | 3 | PSYGENET |
| Hgene | RARA | C0006142 | Malignant neoplasm of breast | 1 | CTD_human |
| Hgene | RARA | C0009363 | Congenital ocular coloboma (disorder) | 1 | GENOMICS_ENGLAND |
| Hgene | RARA | C0010701 | Phyllodes Tumor | 1 | CTD_human |
| Hgene | RARA | C0085183 | Neoplasms, Second Primary | 1 | CTD_human |
| Hgene | RARA | C0086696 | Neoplasms, Therapy-Associated | 1 | CTD_human |
| Hgene | RARA | C0149940 | Sciatic Neuropathy | 1 | CTD_human |
| Hgene | RARA | C0154748 | Lesion of Sciatic Nerve | 1 | CTD_human |
| Hgene | RARA | C0206650 | Fibroadenoma | 1 | CTD_human |
| Hgene | RARA | C0242013 | Sciatic Neuritis | 1 | CTD_human |
| Hgene | RARA | C0525045 | Mood Disorders | 1 | PSYGENET |
| Hgene | RARA | C0600066 | Malignant Cystosarcoma Phyllodes | 1 | CTD_human |
| Hgene | RARA | C0678222 | Breast Carcinoma | 1 | CTD_human |
| Hgene | RARA | C0751924 | Neuralgia-Neuritis, Sciatic Nerve | 1 | CTD_human |
| Hgene | RARA | C0751925 | Sciatic Nerve Palsy | 1 | CTD_human |
| Hgene | RARA | C0877578 | Treatment related secondary malignancy | 1 | CTD_human |
| Hgene | RARA | C1257931 | Mammary Neoplasms, Human | 1 | CTD_human |
| Hgene | RARA | C1458155 | Mammary Neoplasms | 1 | CTD_human |
| Hgene | RARA | C2239176 | Liver carcinoma | 1 | CTD_human |
| Hgene | RARA | C4704874 | Mammary Carcinoma, Human | 1 | CTD_human |
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