| Accession_id | Subsection | Start | End | Funcitonal feature | Splicing information |
| Q01081 | Domain | 65 | 147 | Note=RRM;Ontology_term=ECO:0000255;evidence=ECO:0000255|PROSITE-ProRule:PRU00176 | Type=Substitution;Start=47;End=66 |
| Q01081 | Domain | 65 | 147 | Note=RRM;Ontology_term=ECO:0000255;evidence=ECO:0000255|PROSITE-ProRule:PRU00176 | Type=Substitution;Start=47;End=66 |
| Q01081 | Domain | 65 | 147 | Note=RRM;Ontology_term=ECO:0000255;evidence=ECO:0000255|PROSITE-ProRule:PRU00176 | Type=Substitution;Start=67;End=75 |
| Q01081 | Domain | 65 | 147 | Note=RRM;Ontology_term=ECO:0000255;evidence=ECO:0000255|PROSITE-ProRule:PRU00176 | Type=Deletion;Start=76;End=240 |
| Q01081 | Domain | 65 | 147 | Note=RRM;Ontology_term=ECO:0000255;evidence=ECO:0000255|PROSITE-ProRule:PRU00176 | Type=Deletion;Start=1;End=73 |
| Q01081 | Zinc finger | 12 | 40 | Note=C3H1-type 1;Ontology_term=ECO:0000255;evidence=ECO:0000255|PROSITE-ProRule:PRU00723 | Type=Deletion;Start=1;End=73 |
| Q01081 | Zinc finger | 149 | 176 | Note=C3H1-type 2;Ontology_term=ECO:0000255;evidence=ECO:0000255|PROSITE-ProRule:PRU00723 | Type=Deletion;Start=76;End=240 |
| Q01081 | Region | 183 | 240 | Note=Disordered;Ontology_term=ECO:0000256;evidence=ECO:0000256|SAM:MobiDB-lite | Type=Deletion;Start=76;End=240 |
| Q01081 | Compositional bias | 185 | 205 | Note=Basic residues;Ontology_term=ECO:0000256;evidence=ECO:0000256|SAM:MobiDB-lite | Type=Deletion;Start=76;End=240 |
| Q01081 | Compositional bias | 222 | 240 | Note=Basic and acidic residues;Ontology_term=ECO:0000256;evidence=ECO:0000256|SAM:MobiDB-lite | Type=Deletion;Start=76;End=240 |
| UniProt-id | Site score | Size | D score | Volume | Exposure | Enclosure | Contact | Phobic | Philic | Balance | Don/Acc | Residues |
| Q01081-1 | 0.944 | 84 | 0.953 | 206.486 | 0.592 | 0.691 | 1.041 | 0.767 | 0.992 | 0.773 | 0.978 | 78,82,98,99,100,101,154,155,156,158,159,172,173,17
4,175,176,177,179,182,183,186,187,190
|
| Q01081-2 | 0.963 | 102 | 0.987 | 238.385 | 0.611 | 0.64 | 0.938 | 0.534 | 1.033 | 0.517 | 0.775 | 78,82,98,99,100,101,151,154,155,158,159,172,173,17
4,175,176,177,178,179,182,183,186,187,190
|
| Q01081-3 | 0.87 | 69 | 0.89 | 128.282 | 0.517 | 0.624 | 0.834 | 0.47 | 0.814 | 0.578 | 0.697 | 50,52,53,54,57,58,66,67,68,69,71,72
|
| Q01081-4 | 1.046 | 234 | 1.091 | 519.988 | 0.481 | 0.708 | 0.912 | 1.187 | 0.84 | 1.414 | 1.046 | 8,12,15,16,38,39,40,41,42,43,44,46,47,50,51,53,54,
57,62,65,66,67,68,69,70,71,72,73,74,75,77
|
| Gene | PMID | Title | Abstract | MeSH ID | MeSH term |
| U2AF1 | 23775717 | Patterns of missplicing due to somatic U2AF1 mutations in myeloid neoplasms. | Recently, recurrent mutations of spliceosomal genes were frequently identified in myeloid malignancies, as well as other types of cancers. One of these spliceosomal genes, U2AF1, was affected by canonical somatic mutations in aggressive type of myeloid malignancies. We hypothesized that U2AF1 mutations causes defects of splicing (missplicing) in specific genes and that such misspliced genes might be important in leukemogenesis. We analyzed RNA deep sequencing to compare splicing patterns of 201 837 exons between the cases with U2AF1 mutations (n = 6) and wild type (n = 14). We identified different alternative splicing patterns in 35 genes comparing cells with mutant and wild-type U2AF1. U2AF1 mutations are associated with abnormal splicing of genes involved in functionally important pathways, such as cell cycle progression and RNA processing. In addition, many of these genes are somatically mutated or deleted in various cancers. Of note is that the alternative splicing patterns associated with U2AF1 mutations were associated with specific sequence signals at the affected splice sites. These novel observations support the hypothesis that U2AF1 mutations play a significant role in myeloid leukemogenesis due to selective missplicing of tumor-associated genes. | D019337 | Hematologic Neoplasms |
| U2AF1 | 23775717 | Patterns of missplicing due to somatic U2AF1 mutations in myeloid neoplasms. | Recently, recurrent mutations of spliceosomal genes were frequently identified in myeloid malignancies, as well as other types of cancers. One of these spliceosomal genes, U2AF1, was affected by canonical somatic mutations in aggressive type of myeloid malignancies. We hypothesized that U2AF1 mutations causes defects of splicing (missplicing) in specific genes and that such misspliced genes might be important in leukemogenesis. We analyzed RNA deep sequencing to compare splicing patterns of 201 837 exons between the cases with U2AF1 mutations (n = 6) and wild type (n = 14). We identified different alternative splicing patterns in 35 genes comparing cells with mutant and wild-type U2AF1. U2AF1 mutations are associated with abnormal splicing of genes involved in functionally important pathways, such as cell cycle progression and RNA processing. In addition, many of these genes are somatically mutated or deleted in various cancers. Of note is that the alternative splicing patterns associated with U2AF1 mutations were associated with specific sequence signals at the affected splice sites. These novel observations support the hypothesis that U2AF1 mutations play a significant role in myeloid leukemogenesis due to selective missplicing of tumor-associated genes. | D015470 | Leukemia, Myeloid, Acute |
| U2AF1 | 23775717 | Patterns of missplicing due to somatic U2AF1 mutations in myeloid neoplasms. | Recently, recurrent mutations of spliceosomal genes were frequently identified in myeloid malignancies, as well as other types of cancers. One of these spliceosomal genes, U2AF1, was affected by canonical somatic mutations in aggressive type of myeloid malignancies. We hypothesized that U2AF1 mutations causes defects of splicing (missplicing) in specific genes and that such misspliced genes might be important in leukemogenesis. We analyzed RNA deep sequencing to compare splicing patterns of 201 837 exons between the cases with U2AF1 mutations (n = 6) and wild type (n = 14). We identified different alternative splicing patterns in 35 genes comparing cells with mutant and wild-type U2AF1. U2AF1 mutations are associated with abnormal splicing of genes involved in functionally important pathways, such as cell cycle progression and RNA processing. In addition, many of these genes are somatically mutated or deleted in various cancers. Of note is that the alternative splicing patterns associated with U2AF1 mutations were associated with specific sequence signals at the affected splice sites. These novel observations support the hypothesis that U2AF1 mutations play a significant role in myeloid leukemogenesis due to selective missplicing of tumor-associated genes. | D009190 | Myelodysplastic Syndromes |
| U2AF1 | 23775717 | Patterns of missplicing due to somatic U2AF1 mutations in myeloid neoplasms. | Recently, recurrent mutations of spliceosomal genes were frequently identified in myeloid malignancies, as well as other types of cancers. One of these spliceosomal genes, U2AF1, was affected by canonical somatic mutations in aggressive type of myeloid malignancies. We hypothesized that U2AF1 mutations causes defects of splicing (missplicing) in specific genes and that such misspliced genes might be important in leukemogenesis. We analyzed RNA deep sequencing to compare splicing patterns of 201 837 exons between the cases with U2AF1 mutations (n = 6) and wild type (n = 14). We identified different alternative splicing patterns in 35 genes comparing cells with mutant and wild-type U2AF1. U2AF1 mutations are associated with abnormal splicing of genes involved in functionally important pathways, such as cell cycle progression and RNA processing. In addition, many of these genes are somatically mutated or deleted in various cancers. Of note is that the alternative splicing patterns associated with U2AF1 mutations were associated with specific sequence signals at the affected splice sites. These novel observations support the hypothesis that U2AF1 mutations play a significant role in myeloid leukemogenesis due to selective missplicing of tumor-associated genes. | D009196 | Myeloproliferative Disorders |
| U2AF1 | 24711643 | Identifying biological pathways that underlie primordial short stature using network analysis. | Mutations in CUL7, OBSL1 and CCDC8, leading to disordered ubiquitination, cause one of the commonest primordial growth disorders, 3-M syndrome. This condition is associated with i) abnormal p53 function, ii) GH and/or IGF1 resistance, which may relate to failure to recycle signalling molecules, and iii) cellular IGF2 deficiency. However the exact molecular mechanisms that may link these abnormalities generating growth restriction remain undefined. In this study, we have used immunoprecipitation/mass spectrometry and transcriptomic studies to generate a 3-M 'interactome', to define key cellular pathways and biological functions associated with growth failure seen in 3-M. We identified 189 proteins which interacted with CUL7, OBSL1 and CCDC8, from which a network including 176 of these proteins was generated. To strengthen the association to 3-M syndrome, these proteins were compared with an inferred network generated from the genes that were differentially expressed in 3-M fibroblasts compared with controls. This resulted in a final 3-M network of 131 proteins, with the most significant biological pathway within the network being mRNA splicing/processing. We have shown using an exogenous insulin receptor (INSR) minigene system that alternative splicing of exon 11 is significantly changed in HEK293 cells with altered expression of CUL7, OBSL1 and CCDC8 and in 3-M fibroblasts. The net result is a reduction in the expression of the mitogenic INSR isoform in 3-M syndrome. From these preliminary data, we hypothesise that disordered ubiquitination could result in aberrant mRNA splicing in 3-M; however, further investigation is required to determine whether this contributes to growth failure. | D004392 | Dwarfism |
| U2AF1 | 24711643 | Identifying biological pathways that underlie primordial short stature using network analysis. | Mutations in CUL7, OBSL1 and CCDC8, leading to disordered ubiquitination, cause one of the commonest primordial growth disorders, 3-M syndrome. This condition is associated with i) abnormal p53 function, ii) GH and/or IGF1 resistance, which may relate to failure to recycle signalling molecules, and iii) cellular IGF2 deficiency. However the exact molecular mechanisms that may link these abnormalities generating growth restriction remain undefined. In this study, we have used immunoprecipitation/mass spectrometry and transcriptomic studies to generate a 3-M 'interactome', to define key cellular pathways and biological functions associated with growth failure seen in 3-M. We identified 189 proteins which interacted with CUL7, OBSL1 and CCDC8, from which a network including 176 of these proteins was generated. To strengthen the association to 3-M syndrome, these proteins were compared with an inferred network generated from the genes that were differentially expressed in 3-M fibroblasts compared with controls. This resulted in a final 3-M network of 131 proteins, with the most significant biological pathway within the network being mRNA splicing/processing. We have shown using an exogenous insulin receptor (INSR) minigene system that alternative splicing of exon 11 is significantly changed in HEK293 cells with altered expression of CUL7, OBSL1 and CCDC8 and in 3-M fibroblasts. The net result is a reduction in the expression of the mitogenic INSR isoform in 3-M syndrome. From these preliminary data, we hypothesise that disordered ubiquitination could result in aberrant mRNA splicing in 3-M; however, further investigation is required to determine whether this contributes to growth failure. | D006130 | Growth Disorders |
| U2AF1 | 24711643 | Identifying biological pathways that underlie primordial short stature using network analysis. | Mutations in CUL7, OBSL1 and CCDC8, leading to disordered ubiquitination, cause one of the commonest primordial growth disorders, 3-M syndrome. This condition is associated with i) abnormal p53 function, ii) GH and/or IGF1 resistance, which may relate to failure to recycle signalling molecules, and iii) cellular IGF2 deficiency. However the exact molecular mechanisms that may link these abnormalities generating growth restriction remain undefined. In this study, we have used immunoprecipitation/mass spectrometry and transcriptomic studies to generate a 3-M 'interactome', to define key cellular pathways and biological functions associated with growth failure seen in 3-M. We identified 189 proteins which interacted with CUL7, OBSL1 and CCDC8, from which a network including 176 of these proteins was generated. To strengthen the association to 3-M syndrome, these proteins were compared with an inferred network generated from the genes that were differentially expressed in 3-M fibroblasts compared with controls. This resulted in a final 3-M network of 131 proteins, with the most significant biological pathway within the network being mRNA splicing/processing. We have shown using an exogenous insulin receptor (INSR) minigene system that alternative splicing of exon 11 is significantly changed in HEK293 cells with altered expression of CUL7, OBSL1 and CCDC8 and in 3-M fibroblasts. The net result is a reduction in the expression of the mitogenic INSR isoform in 3-M syndrome. From these preliminary data, we hypothesise that disordered ubiquitination could result in aberrant mRNA splicing in 3-M; however, further investigation is required to determine whether this contributes to growth failure. | D009123 | Muscle Hypotonia |
| U2AF1 | 35434831 | U2AF1 mutation connects DNA damage to the alternative splicing of RAD51 in lung adenocarcinomas. | The recurrent mutation (S34F) in splicing factor U2AF1 is frequently observed in lung adenocarcinoma, but its function remains largely unknown. To determine the mechanistic basis and consequences of U2AF1 mutations, we established non-small cell lung carcinoma A549 cell lines with exogenous expression of wildtype (U2AF1-WT) or mutant (U2AF1-S34F). Splicing analysis revealed that U2AF1-S34F mainly caused aberrant exon usage and affected splicing of numerous DNA damage repair genes. Compared to A549 cells expressing U2AF1-WT, cells expressing U2AF1-S34F showed enhanced DNA damage and cell death in response to ATR inhibitors (ATRi). Mechanistically, U2AF1-S34F induced mis-splicing and downregulation of a key homologous recombination protein RAD51. Overexpression of RAD51 could largely rescue the defective DNA damage response in cells expressing U2AF1-S34F. Moreover, A549 cells expressing U2AF1-S34F, but not U2AF1-WT, were highly sensitive to treatment even with low dose of RAD51 inhibitor on ATRi-induced DNA damage. Our results suggest that U2AF1-S34F causes mis-splicing of DNA damage repair factors in lung cancer and sensitizes cells to RAD51 inhibition. | D000077192 | Adenocarcinoma of Lung |
| U2AF1 | 35434831 | U2AF1 mutation connects DNA damage to the alternative splicing of RAD51 in lung adenocarcinomas. | The recurrent mutation (S34F) in splicing factor U2AF1 is frequently observed in lung adenocarcinoma, but its function remains largely unknown. To determine the mechanistic basis and consequences of U2AF1 mutations, we established non-small cell lung carcinoma A549 cell lines with exogenous expression of wildtype (U2AF1-WT) or mutant (U2AF1-S34F). Splicing analysis revealed that U2AF1-S34F mainly caused aberrant exon usage and affected splicing of numerous DNA damage repair genes. Compared to A549 cells expressing U2AF1-WT, cells expressing U2AF1-S34F showed enhanced DNA damage and cell death in response to ATR inhibitors (ATRi). Mechanistically, U2AF1-S34F induced mis-splicing and downregulation of a key homologous recombination protein RAD51. Overexpression of RAD51 could largely rescue the defective DNA damage response in cells expressing U2AF1-S34F. Moreover, A549 cells expressing U2AF1-S34F, but not U2AF1-WT, were highly sensitive to treatment even with low dose of RAD51 inhibitor on ATRi-induced DNA damage. Our results suggest that U2AF1-S34F causes mis-splicing of DNA damage repair factors in lung cancer and sensitizes cells to RAD51 inhibition. | D008175 | Lung Neoplasms |
Gene summary
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