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Journal articles on the topic 'UBAP2L'

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Author: Grafiati

Published: 23 September 2022

Last updated: 28 September 2022

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1

Ye, Tao, Jing Xu, Ling Du, Wenhui Mo, Yiming Liang, and Jinglin Xia. "Downregulation of UBAP2L Inhibits the Epithelial-Mesenchymal Transition via SNAIL1 Regulation in Hepatocellular Carcinoma Cells." Cellular Physiology and Biochemistry 41, no. 4 (2017): 1584–95. http://dx.doi.org/10.1159/000470824.

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Background/Aims: Dysregulation of ubiquitin-associated protein 2-like (UBAP2L) has been reported in tumors, but its role in hepatocellular carcinoma (HCC) progression is unclear. Methods: The expression levels of UBAP2L in HCC tissues and HCC cell lines were detected by western blot and quantitative real-time (qRT) PCR. The effects of UBAP2L expression on HCC cell biological traits, including migration and invasion, were investigated by wound healing assay and matrigel transwell assay. Simultaneously, the expression of epithelial-mesenchymal transition (EMT) markers including E-cadherin, CK-18, N-cadherin, Vimentin, Claudin7 and the promoter activity of E-cadherin were detected by western blot and qRT-PCR. Subsequently, role of SNAIL1 in UBAP2L-mediated EMT and the mechanism underlying UBAP2L-mediated SNAIL1 expression were further investigated. Results: UBAP2L was overexpressed in human HCC tissues compared with peri-tumoral tissues. Downregulation of UBAP2L inhibited migration, invasion and the EMT in highly metastatic HCC cell lines. Furthermore, UBAP2L knockdown inhibited expression of the transcriptional repressor SNAIL1 and its ability to bind to the E-cadherin promoter via SMAD2 signaling pathway, which in turn resulted in increased E-cadherin expression. Additionally, bioinformatics analysis showed that expression of UBAP2L is correlated with poor prognosis in patients with HCC. Conclusions: UBAP2L plays a critical role in maintenance of the metastatic ability of HCC cells via SNAIL1 Regulation and is predictive of a poor clinical outcome.

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2

Bordeleau, Marie-Eve, Jalila Chagraoui, Romain Aucagne, Simon Girard, Éric Bonneil, Martin Sauvageau, Amélie Faubert, Pierre Thibault, and Guy Sauvageau. "Ubap2l-Bmi-1-Rnf2 Define a Novel Polycomb Complex Essential For Self-Renewal Of Hematopoietic Stem Cells." Blood 122, no. 21 (November 15, 2013): 736. http://dx.doi.org/10.1182/blood.v122.21.736.736.

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Abstract The polycomb group protein Bmi-1 is a well known determinant of hematopoietic stem cell function. Bmi-1-/- mice display severe hematopoietic defects, including progressive loss of hematopoietic cells from the bone marrow. Bmi-1 is dispensable for hematopoietic stem cell specification, but essential for their maintenance, an effect attributable to its ability to promote HSC self-renewal. The mechanism by which Bmi-1 regulates this process is not completely understood. Bmi-1 has been shown to repress the INK4A/ARF locus encoding the cell cycle inhibitors p16ink4a and p19arf , to interact with the E4F1 protein and to regulate the DNA damage response pathway, however experimental manipulation of these proteins/pathways only partially rescues the hematopoietic defects of the Bmi-1-/-mice. It thus appears that the mechanism by which Bmi-1 regulates HSC self-renewal remains to be determined. Towards this goal, we purified Bmi-1 containing protein complexes from cellular extracts and identified Bmi-1 interaction partners by mass spectrometry. We observed that the protein Ubap2l, which has never been shown to associate with Bmi-1 and for which no link with polycomb group protein function has been described, was consistently found in Bmi-1-containing protein complexes. Immunoprecipitation experiments revealed that Ubap2l indirectly associates with Bmi-1 via an interaction with the polycomb group protein Rnf2. We then evaluated the possibility that Ubap2l might be involved in the regulation of HSC activity. We observed that Ubap2l transcripts are more abundant in primitive HSC populations compared to total BM. CFC assays performed with BM cells infected with Ubap2l shRNAs revealed that Ubap2l knockdown causes a modest and progressive loss of progenitor activity when cells are kept in culture, with multipotent and bipotent progenitors being substantially more affected than unipotent progenitors. We transplanted these cells in mice and observed a gradual decrease in the percentage of donor derived cells expressing Ubap2l shRNAs in the peripheral blood of the recipient mice, with the most striking effect observed 16 weeks post-transplantation in the BM. Bmi-1 has been shown to regulate the proliferative capacity of both progenitor and stem cells, and its deletion in BM cells is known to dramatically reduce the reconstitution activity of these cells at early time points following transplantation. In contrast, Ubap2l appears to preferentially regulate LTR-HSC activity. We tested the effects of Ubap2l silencing on leukemic cells in vivo and observed that a reduction of Ubap2l levels in these cells had an important impact on their ability to reconstitute recipient mice, suggesting that Ubap2l also plays a role in leukemic stem cell activity. We determined if the mechanism by which Ubap2l regulates HSC activity is related to Bmi-1 function by simultaneously introducing Bmi-1 cDNA and Ubap2l shRNAs in BM cells and found that Bmi-1 is able to rescue the long-term reconstitution defect caused by Ubap2l downregulation in these cells. We observed that Ubap2l silencing does not significantly affect the expression of the known Bmi-1 targets p16ink4a and p19arf, implying that Ubap2l regulates HSC activity via a Bmi-1-dependent mechanism that does not involve repression of the INK4A/ARF locus. One explanation for the two Bmi-1 dependent mechanisms at play in the regulation of HSC activity could be that Bmi-1 is part of two separate protein complexes, each regulating different aspects of hematopoietic cell function. To test this hypothesis, we fractionated cellular extracts and were indeed able to resolve two distinct Bmi-1 containing protein complexes, distinguishable by the presence of Ubap2l. Based on the results we obtained, we propose a model in which two different Bmi-1 containing protein complexes regulate hematopoietic stem cell function. An Ubap2l-independent complex, which is most likely involved in the repression of the INK4A/ARF locus, and could be responsible for the effects of Bmi-1 on multipotent progenitors and STR-HSCs, and an Ubap2l-dependent complex, which operates via a yet to be defined mechanism unrelated to p16Ink4a and p19Arf, and would account for the effects of Bmi-1 on LTR-HSC activity. These results position Ubap2l as a key regulator of LTR-HSC activity and unveil a novel protein complex mediating the effects of Bmi-1 on LTR-HSCs. Disclosures: No relevant conflicts of interest to declare.

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3

Bordeleau, Marie-Eve, Romain Aucagne, Jalila Chagraoui, Simon Girard, Nadine Mayotte, Éric Bonneil, Pierre Thibault, et al. "UBAP2L is a novel BMI1-interacting protein essential for hematopoietic stem cell activity." Blood 124, no. 15 (October 9, 2014): 2362–69. http://dx.doi.org/10.1182/blood-2014-01-548651.

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4

Carlston, Colleen, Robin Weinmann, Natalia Stec, Simona Abbatemarco, Francoise Schwager, Jing Wang, Huiwu Ouyang, Collin Y. Ewald, Monica Gotta, and Christopher M. Hammell. "PQN-59 antagonizes microRNA-mediated repression during post-embryonic temporal patterning and modulates translation and stress granule formation in C. elegans." PLOS Genetics 17, no. 11 (November 22, 2021): e1009599. http://dx.doi.org/10.1371/journal.pgen.1009599.

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microRNAs (miRNAs) are potent regulators of gene expression that function in a variety of developmental and physiological processes by dampening the expression of their target genes at a post-transcriptional level. In many gene regulatory networks (GRNs), miRNAs function in a switch-like manner whereby their expression and activity elicit a transition from one stable pattern of gene expression to a distinct, equally stable pattern required to define a nascent cell fate. While the importance of miRNAs that function in this capacity are clear, we have less of an understanding of the cellular factors and mechanisms that ensure the robustness of this form of regulatory bistability. In a screen to identify suppressors of temporal patterning phenotypes that result from ineffective miRNA-mediated target repression, we identified pqn-59, an ortholog of human UBAP2L, as a novel factor that antagonizes the activities of multiple heterochronic miRNAs. Specifically, we find that depletion of pqn-59 can restore normal development in animals with reduced lin-4 and let-7-family miRNA activity. Importantly, inactivation of pqn-59 is not sufficient to bypass the requirement of these regulatory RNAs within the heterochronic GRN. The pqn-59 gene encodes an abundant, cytoplasmically-localized, unstructured protein that harbors three essential “prion-like” domains. These domains exhibit LLPS properties in vitro and normally function to limit PQN-59 diffusion in the cytoplasm in vivo. Like human UBAP2L, PQN-59’s localization becomes highly dynamic during stress conditions where it re-distributes to cytoplasmic stress granules and is important for their formation. Proteomic analysis of PQN-59 complexes from embryonic extracts indicates that PQN-59 and human UBAP2L interact with orthologous cellular components involved in RNA metabolism and promoting protein translation and that PQN-59 additionally interacts with proteins involved in transcription and intracellular transport. Finally, we demonstrate that pqn-59 depletion reduces protein translation and also results in the stabilization of several mature miRNAs (including those involved in temporal patterning). These data suggest that PQN-59 may ensure the bistability of some GRNs that require miRNA functions by promoting miRNA turnover and, like UBAP2L, enhancing protein translation.

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5

Huang, Chuyu, Yan Chen, Huaiqian Dai, Huan Zhang, Minyu Xie, Hanbin Zhang, Feilong Chen, Xiangjin Kang, Xiaochun Bai, and Zhenguo Chen. "UBAP2L arginine methylation by PRMT1 modulates stress granule assembly." Cell Death & Differentiation 27, no. 1 (May 21, 2019): 227–41. http://dx.doi.org/10.1038/s41418-019-0350-5.

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6

He, Jing, Yuanping Chen, Lu Cai, Zelei Li, and Xiaoqing Guo. "UBAP2L silencing inhibits cell proliferation and G2/M phase transition in breast cancer." Breast Cancer 25, no. 2 (December 1, 2017): 224–32. http://dx.doi.org/10.1007/s12282-017-0820-x.

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7

Cirillo, Luca, Adeline Cieren, Sofia Barbieri, Anthony Khong, Françoise Schwager, Roy Parker, and Monica Gotta. "UBAP2L Forms Distinct Cores that Act in Nucleating Stress Granules Upstream of G3BP1." Current Biology 30, no. 4 (February 2020): 698–707. http://dx.doi.org/10.1016/j.cub.2019.12.020.

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8

Huang, Rui, Qixia Yang, and Tiantian Wang. "Norcantharidin-blocked ANXA2P2 inhibits fibroblast proliferation by increasing UBAP2L mRNA stability through LIN28B." Life Sciences 279 (August 2021): 119645. http://dx.doi.org/10.1016/j.lfs.2021.119645.

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9

Lin, Sihan, Zhiyong Yan, Qiaofei Tang, and Shuang Zhang. "Ubiquitin-associated protein 2 like (UBAP2L) enhances growth and metastasis of gastric cancer cells." Bioengineered 12, no. 2 (November 25, 2021): 10232–45. http://dx.doi.org/10.1080/21655979.2021.1982308.

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10

Li, Qian, Wei Wang, Yu-Chen Hu, Tian-Tian Yin, and Jie He. "Knockdown of Ubiquitin Associated Protein 2-Like (UBAP2L) Inhibits Growth and Metastasis of Hepatocellular Carcinoma." Medical Science Monitor 24 (October 6, 2018): 7109–18. http://dx.doi.org/10.12659/msm.912861.

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11

Sazanov, A. A., A. L. Sazanova, V. A. Stekolnikova, A. V. Trukhina, A. A. Kozyreva, A. F. Smirnov, M. N. Romanov, L. J. L. Handley, T. Malewski, and J. B. Dodgson. "Chromosomal localization of the UBAP2Z and UBAP2W genes in chicken." Animal Genetics 37, no. 1 (February 2006): 72–73. http://dx.doi.org/10.1111/j.1365-2052.2005.01392.x.

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12

Wang, Wei, Min Zhang, Yan Peng, and Jie He. "Ubiquitin Associated Protein 2-Like (UBAP2L) Overexpression in Patients with Hepatocellular Carcinoma and its Clinical Significance." Medical Science Monitor 23 (October 5, 2017): 4779–88. http://dx.doi.org/10.12659/msm.907071.

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13

An, Haiyan, Jing Tong Tan, and Tatyana A. Shelkovnikova. "Stress granules regulate stress-induced paraspeckle assembly." Journal of Cell Biology 218, no. 12 (October 21, 2019): 4127–40. http://dx.doi.org/10.1083/jcb.201904098.

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Eukaryotic cells contain a variety of RNA-protein macrocomplexes termed RNP granules. Different types of granules share multiple protein components; however, the crosstalk between spatially separated granules remains unaddressed. Paraspeckles and stress granules (SGs) are prototypical RNP granules localized exclusively in the nucleus and cytoplasm, respectively. Both granules are implicated in human diseases, such as amyotrophic lateral sclerosis. We characterized the composition of affinity-purified paraspeckle-like structures and found a significant overlap between the proteomes of paraspeckles and SGs. We further show that paraspeckle hyperassembly is typical for cells subjected to SG-inducing stresses. Using chemical and genetic disruption of SGs, we demonstrate that formation of microscopically visible SGs is required to trigger and maintain stress-induced paraspeckle assembly. Mechanistically, SGs may sequester negative regulators of paraspeckle formation, such as UBAP2L, alleviating their inhibitory effect on paraspeckles. Our study reveals a novel function for SGs as positive regulators of nuclear RNP granule assembly and suggests a role for disturbed SG-paraspeckle crosstalk in human disease.

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14

Lin, Guan-lin, Huan Wang, Jun Dai, Xiao Li, Ming Guan, Qing Ding, Huai-xi Wang, and Huang Fang. "Upregulation of UBAP2L in Bone Marrow Mesenchymal Stem Cells Promotes Functional Recovery in Rats with Spinal Cord Injury." Current Medical Science 38, no. 6 (December 2018): 1081–89. http://dx.doi.org/10.1007/s11596-018-1987-x.

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15

Yang, Zhiwei, Guoyin Li, Yizhen Zhao, Lei Zhang, Xiaohui Yuan, Lingjie Meng, Huadong Liu, Yong Han, Lintao Jia, and Shengli Zhang. "Molecular Insights into the Recruiting Between UCP2 and DDX5/UBAP2L in the Metabolic Plasticity of Non-Small-Cell Lung Cancer." Journal of Chemical Information and Modeling 61, no. 8 (July 26, 2021): 3978–87. http://dx.doi.org/10.1021/acs.jcim.1c00138.

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16

Aucagne, Romain, Simon Girard, Nadine Mayotte, Bernhard Lehnertz, Stéphane Lopes‐Paciencia, Patrick Gendron, Geneviève Boucher, Jalila Chagraoui, and Guy Sauvageau. "UBAP2L is amplified in a large subset of human lung adenocarcinoma and is critical for epithelial lung cell identity and tumor metastasis." FASEB Journal 31, no. 11 (July 28, 2017): 5012–18. http://dx.doi.org/10.1096/fj.201601219rrr.

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17

Guan, Mengqi, Daian Pan, Mei Zhang, Xiangyang Leng, and Baojin Yao. "The Aqueous Extract of Eucommia Leaves Promotes Proliferation, Differentiation, and Mineralization of Osteoblast-Like MC3T3-E1 Cells." Evidence-Based Complementary and Alternative Medicine 2021 (June 19, 2021): 1–12. http://dx.doi.org/10.1155/2021/3641317.

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Eucommia leaves are dry leaves of Eucommia ulmoides which have long been considered as a functional health food for the treatment of hypertension, hypercholesterolemia, fatty liver, and osteoporosis. With the recent development of Chinese medicine, Eucommia leaves are widely used for tonifying the kidneys and strengthening bone. However, the specific molecular mechanism of Eucommia leaves for strengthening bone remains largely unknown. Osteoblasts are the main functional cells of bone formation; thus, it is essential to study the effect of Eucommia leaves on osteoblasts to better understand their mechanism of action. In the present study, we prepared an aqueous extract of Eucommia leaves (ELAE) and determined its content by high-performance liquid chromatography (HPLC). The effects of ELAE on MC3T3-E1 cells were investigated by CCK-8 assay, alkaline phosphatase (ALP), and Alizarin red S staining assays, combined with RNA sequencing (RNA-seq) and qRT-PCR validation. We demonstrated that ELAE had a significant promoting effect on the proliferation of MC3T3-E1 cells and significantly enhanced extracellular matrix synthesis and mineralization, which were achieved by regulating various functional genes and related signaling pathways. ELAE significantly increased the expression level of genes promoting cell proliferation, such as Rpl10a, Adnp, Pex1, Inpp4a, Frat2, and Pcdhga1, and reduced the expression level of genes inhibiting cell proliferation, such as Npm1, Eif3e, Cbx3, Psmc6, Fgf7, Fxr1, Ddx3x, Mbnl1, and Cdc27. In addition, ELAE increased the expression level of gene markers in osteoblasts, such as Col5a2, Ubap2l, Dkk3, Foxm1, Col16a1, Col12a1, Usp7, Col4a6, Runx2, Sox4, and Bmp4. Taken together, our results suggest that ELAE could promote osteoblast proliferation, differentiation, and mineralization and prevent osteoblast apoptosis. These findings not only increase our understanding of ELAE on the regulation of bone development but also provide a possible strategy to further study the prevention and treatment of osteogenic related diseases by ELAE.

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18

Nasir, Amjad M., Qianyi Yang, Douglas L. Chalker, and James D. Forney. "SUMOylation Is Developmentally Regulated and Required for Cell Pairing during Conjugation in Tetrahymena thermophila." Eukaryotic Cell 14, no. 2 (December 19, 2014): 170–81. http://dx.doi.org/10.1128/ec.00252-14.

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ABSTRACT The covalent attachment of s mall u biquitin-like mo difier (SUMO) to target proteins regulates numerous nuclear events in eukaryotes, including transcription, mitosis and meiosis, and DNA repair. Despite extensive interest in nuclear pathways within the field of ciliate molecular biology, there have been no investigations of the SUMO pathway in Tetrahymena . The developmental program of sexual reproduction of this organism includes cell pairing, micronuclear meiosis, and the formation of a new somatic macronucleus. We identified the Tetrahymena thermophila SMT3 (SUMO) and UBA2 (SUMO-activating enzyme) genes and demonstrated that the corresponding green fluorescent protein (GFP) tagged gene products are found predominantly in the somatic macronucleus during vegetative growth. Use of an anti-Smt3p antibody to perform immunoblot assays with whole-cell lysates during conjugation revealed a large increase in SUMOylation that peaked during formation of the new macronucleus. Immunofluorescence using the same antibody showed that the increase was localized primarily within the new macronucleus. To initiate functional analysis of the SUMO pathway, we created germ line knockout cell lines for both the SMT3 and UBA2 genes and found both are essential for cell viability. Conditional Smt3p and Uba2p cell lines were constructed by incorporation of the cadmium-inducible metallothionein promoter. Withdrawal of cadmium resulted in reduced cell growth and increased sensitivity to DNA-damaging agents. Interestingly, Smt3p and Uba2p conditional cell lines were unable to pair during sexual reproduction in the absence of cadmium, consistent with a function early in conjugation. Our studies are consistent with multiple roles for SUMOylation in Tetrahymena , including a dynamic regulation associated with the sexual life cycle.

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19

Shih, Hsin-Pei, Karen G. Hales, John R. Pringle, and Mark Peifer. "Identification of septin-interacting proteins and characterization of the Smt3/SUMO-conjugation system inDrosophila." Journal of Cell Science 115, no. 6 (March 15, 2002): 1259–71. http://dx.doi.org/10.1242/jcs.115.6.1259.

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The septins are a family of proteins involved in cytokinesis and other aspects of cell-cortex organization. In a two-hybrid screen designed to identify septin-interacting proteins in Drosophila, we isolated several genes, including homologues (Dmuba2 and Dmubc9) of yeast UBA2 and UBC9. Yeast Uba2p and Ubc9p are involved in the activation and conjugation, respectively, of the ubiquitin-like protein Smt3p/SUMO, which becomes conjugated to a variety of proteins through this pathway. Uba2p functions together with a second protein, Aos1p. We also cloned and characterized the Drosophila homologues of AOS1(Dmaos1) and SMT3 (Dmsmt3). Our biochemical data suggest that DmUba2/DmAos1 and DmUbc9 indeed act as activating and conjugating enzymes for DmSmt3, implying that this protein-conjugation pathway is well conserved in Drosophila. Immunofluorescence studies showed that DmUba2 shuttles between the embryonic cortex and nuclei during the syncytial blastoderm stage. In older embryos, DmUba2 and DmSmt3 are both concentrated in the nuclei during interphase but dispersed throughout the cells during mitosis, with DmSmt3 also enriched on the chromosomes during mitosis. These data suggest that DmSmt3 could modify target proteins both inside and outside the nuclei. We did not observe any concentration of DmUba2 at sites where the septins are concentrated, and we could not detect DmSmt3 modification of the three Drosophila septins tested. However, we did observe DmSmt3 localization to the midbody during cytokinesis both in tissue-culture cells and in embryonic mitotic domains, suggesting that DmSmt3 modification of septins and/or other midzone proteins occurs during cytokinesis in Drosophila.

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20

Lin, Xiang, Hui-Zhen Su, En-Lin Dong, Xiao-Hong Lin, Miao Zhao, Can Yang, Chong Wang, et al. "Stop-gain mutations in UBAP1 cause pure autosomal-dominant spastic paraplegia." Brain 142, no. 8 (June 15, 2019): 2238–52. http://dx.doi.org/10.1093/brain/awz158.

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Abstract Hereditary spastic paraplegias refer to a heterogeneous group of neurodegenerative disorders resulting from degeneration of the corticospinal tract. Clinical characterization of patients with hereditary spastic paraplegias represents progressive spasticity, exaggerated reflexes and muscular weakness. Here, to expand on the increasingly broad pools of previously unknown hereditary spastic paraplegia causative genes and subtypes, we performed whole exome sequencing for six affected and two unaffected individuals from two unrelated Chinese families with an autosomal dominant hereditary spastic paraplegia and lacking mutations in known hereditary spastic paraplegia implicated genes. The exome sequencing revealed two stop-gain mutations, c.247_248insGTGAATTC (p.I83Sfs*11) and c.526G>T (p.E176*), in the ubiquitin-associated protein 1 (UBAP1) gene, which co-segregated with the spastic paraplegia. We also identified two UBAP1 frameshift mutations, c.324_325delCA (p.H108Qfs*10) and c.425_426delAG (p.K143Sfs*15), in two unrelated families from an additional 38 Chinese pedigrees with autosomal dominant hereditary spastic paraplegias and lacking mutations in known causative genes. The primary disease presentation was a pure lower limb predominant spastic paraplegia. In vivo downregulation of Ubap1 in zebrafish causes abnormal organismal morphology, inhibited motor neuron outgrowth, decreased mobility, and shorter lifespan. UBAP1 is incorporated into endosomal sorting complexes required for transport complex I and binds ubiquitin to function in endosome sorting. Patient-derived truncated form(s) of UBAP1 cause aberrant endosome clustering, pronounced endosome enlargement, and cytoplasmic accumulation of ubiquitinated proteins in HeLa cells and wild-type mouse cortical neuron cultures. Biochemical and immunocytochemical experiments in cultured cortical neurons derived from transgenic Ubap1flox mice confirmed that disruption of UBAP1 leads to dysregulation of both early endosome processing and ubiquitinated protein sorting. Strikingly, deletion of Ubap1 promotes neurodegeneration, potentially mediated by apoptosis. Our study provides genetic and biochemical evidence that mutations in UBAP1 can cause pure autosomal dominant spastic paraplegia.

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21

Bian, Xinchao, Guangying Cheng, Xinbo Sun, Hongkun Liu, Xiangmao Zhang, Yu Han, Bo Li, and Ning Li. "Two novel truncating variants in UBAP1 are responsible for hereditary spastic paraplegia." PLOS ONE 16, no. 6 (June 30, 2021): e0253871. http://dx.doi.org/10.1371/journal.pone.0253871.

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Hereditary spastic paraplegias (HSPs) are a group of rare neurodegenerative disorders. HSPs are complex disorders and are clinically and genetically heterogeneous. To date, more than 80 genes or genetic loci have been reported to be responsible for HSPs in a Mendelian-dependent manner. Most recently, ubiquitin-associated protein 1 (UBAP1) has been recognized to be involved in HSP. Here, we identified novel protein truncating variants in two families with pure form of HSP. A novel deletion (c.468_469delTG) in the UBAP1 gene was found in the first family, whereas a nonsense variant (c.512T>G) was ascertained in the second family. The variants were confirmed in all patients but were not detected in unaffected family members. The mutations resulted in truncated proteins of UBAP1. The variants did not result in different subcellular localizations in neuro-2a cells. However, each of the two variants impaired neurite outgrowth. Taken together, our findings expand the pathogenic spectrum of UBAP1 variants in HSP.

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22

Lambermon, Mark H. L., Yu Fu, Dominika A. Wieczorek Kirk, Marcel Dupasquier, Witold Filipowicz, and Zdravko J. Lorković. "UBA1 and UBA2, Two Proteins That Interact with UBP1, a Multifunctional Effector of Pre-mRNA Maturation in Plants." Molecular and Cellular Biology 22, no. 12 (June 15, 2002): 4346–57. http://dx.doi.org/10.1128/mcb.22.12.4346-4357.2002.

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ABSTRACT Nicotiana plumbaginifolia UBP1 is an hnRNP-like protein associated with the poly(A)+ RNA in the cell nucleus. Consistent with a role in pre-mRNA processing, overexpression of UBP1 in N. plumabaginifolia protoplasts enhances the splicing of suboptimal introns and increases the steady-state levels of reporter mRNAs, even intronless ones. The latter effect of UBP1 is promoter specific and appears to be due to UBP1 binding to the 3′ untranslated region (3′-UTR) and protecting the mRNA from exonucleolytic degradation (M. H. L. Lambermon, G. G. Simpson, D. A. Kirk, M. Hemmings-Mieszczak, U. Klahre, and W. Filipowicz, EMBO J. 19:1638-1649, 2000). To gain more insight into UBP1 function in pre-mRNA maturation, we characterized proteins interacting with N. plumbaginifolia UBP1 and one of its Arabidopsis thaliana counterparts, AtUBP1b, by using yeast two-hybrid screens and in vitro pull-down assays. Two proteins, UBP1-associated proteins 1a and 2a (UBA1a and UBA2a, respectively), were identified in A. thaliana. They are members of two novel families of plant-specific proteins containing RNA recognition motif-type RNA-binding domains. UBA1a and UBA2a are nuclear proteins, and their recombinant forms bind RNA with a specificity for oligouridylates in vitro. As with UBP1, transient overexpression of UBA1a in protoplasts increases the steady-state levels of reporter mRNAs in a promoter-dependent manner. Similarly, overexpression of UBA2a increases the levels of reporter mRNAs, but this effect is promoter independent. Unlike UBP1, neither UBA1a nor UBA2a stimulates pre-mRNA splicing. These and other data suggest that UBP1, UBA1a, and UBA2a may act as components of a complex recognizing U-rich sequences in plant 3′-UTRs and contributing to the stabilization of mRNAs in the nucleus.

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23

Nan, Haitian, Yuta Ichinose, Masaki Tanaka, Kishin Koh, Hiroyuki Ishiura, Jun Mitsui, Heisuke Mizukami, et al. "UBAP1 mutations cause juvenile-onset hereditary spastic paraplegias (SPG80) and impair UBAP1 targeting to endosomes." Journal of Human Genetics 64, no. 11 (September 12, 2019): 1055–65. http://dx.doi.org/10.1038/s10038-019-0670-9.

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24

Marchesini, Matteo, Paola Storti, Yamini Ogoti, Marianna D'Anca, Luigi Nezi, Yue Wei, Hui Yang, et al. "ILF2 Is a Regulator of RNA Splicing and DNA Damage Response in 1q21-Amplified Multiple Myeloma." Blood 124, no. 21 (December 6, 2014): 30. http://dx.doi.org/10.1182/blood.v124.21.30.30.

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Abstract In the last decade, significant effort has been directed toward the stratification of multiple myeloma (MM) patients for targeted therapy, and many studies have shown that some genetic alterations, especially t(4;14) translocation, loss of the short arm of chromosome 17, and amplification of chromosome 1q21, are associated with a poor outcome. The 1q21 amplicon spans a region of 10-15 Mb and contains a large number of possible candidate genes; it is among the most frequent chromosomal aberrations in patients with MM and is associated with poor prognosis, disease progression, and drug resistance. Therefore, the identification of critical 1q21 genes may yield potential therapeutic targets for this high-risk MM subgroup and provide a rationale for patient stratification. In an effort to accomplish this goal, we first identified a high-priority list of 78 copy number-driven 1q21 MM-relevant genes by integrating high-resolution array comparative genomic hybridization (aCGH) and matched expression profiling of the 254 MM samples deposited in the Multiple Myeloma Research Consortium (MMRC) database. Then, we performed a high-throughput systematic shRNA screen in vitroto identify 1q21 genes whose loss of function resulted in the selective death and/or growth inhibition of MM cells carrying the 1q21 amplification. We used shRNA targeting (excluding shRNAs that displayed cytotoxic activity regardless of 1q21 amplification) and a GFP competitive growth assay to identify 1q21-resident targets whose downregulation significantly decreased the percentage of GFP-positive MM cells with 1q21 amplification over a time of 7 days. These assays identified UBAPL2, INTS3, LASS2, KRTCAP2, and ILF2 as key targets for further analysis. Secondary validation experiments in the MM cell lines JJN3 and H929 confirmed that the downregulation of all of our top five candidate genes induced significant levels of apoptosis, inhibition of proliferation, and cell cycle arrest. Integration of copy number analysis, expression profiling, and clinical outcome indicated that only UBAPL2 and ILF2 were highly significant prognostic genes, and target validation in NOD-SCID mice showed that ILF2, but not UBAPL2, downregulation had a significant impact on in vivo survival. Therefore, we sought to further characterize ILF2’s role in 1q21-amplified MM. ILF2 encodes NF45, the regulatory subunit of NF90/NF110 complexes, which are involved in mitotic control, DNA break repair, and RNA splicing regulation. Downregulation of ILF2 in MM cells with 1q21 amplification resulted in multinucleated phenotypes and abnormal nuclear morphologies (nucleoplasmic bridges and buds and micronuclei) that were associated with a significant accumulation of phospho-H2AX foci and DNA damage response activation, increased sensitivity to the DNA damaging agent melphalan, and impaired activation of DNA repair pathways. Experiments of immunoprecipitation combined with mass spectometry showed that ILF2 interacts with numerous RNA binding proteins directly implicated in DNA repair or regulation of DNA damage response by modulating alternative splicing and stability of specific pre-mRNAs. Accordingly, RNA-seq analysis of ILF2-depleted MM cells, when compared to cells carrying scrambled shRNAs, identified specific changes in RNA splicing patterns both before and after treatment with melphalan. In conclusion, our studies have revealed an unanticipated link between 1q21 amplification, DNA damage response, and RNA splicing. We identified ILF2 as a key driver of this interaction, and our findings support the development of strategies designed to modulate ILF2 expression in patients with high-risk MM carrying 1q21 amplification. Disclosures No relevant conflicts of interest to declare.

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Wang, Yong, Rongfen Gao, Jinpeng Li, Shaotao Tang, Shuai Li, Qiangsong Tong, and Yongzhong Mao. "Circular RNA hsa_circ_0003141 promotes tumorigenesis of hepatocellular carcinoma via a miR-1827/UBAP2 axis." Aging 12, no. 10 (May 28, 2020): 9793–806. http://dx.doi.org/10.18632/aging.103244.

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Sklavenitis-Pistofidis, Romanos, Mairead Reidy, Daisy Huynh, Karma Ziad Salem, Jihye Park, Siobhan Glavey, Xavier Leleu, David Root, Irene M. Ghobrial, and Salomon Manier. "Founding Precision Therapy in 1q-Amplified Multiple Myeloma." Blood 132, Supplement 1 (November 29, 2018): 1007. http://dx.doi.org/10.1182/blood-2018-99-112673.

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Abstract Introduction Multiple myeloma is an incurable plasma cell malignancy with a strikingly heterogeneous genomic landscape. Other than IgH translocations and hyperdiploidy, only a few alterations are observed in large enough numbers. Amplification of the long arm of chromosome 1 (1q) is among the most common copy number alterations encountered, with a confirmed adverse effect on survival. Gene expression profiling has identified a minimal common amplified region between 1q21 and 1q23 as a probable target of the amplification event, however the actionable gene dependencies in that region have not been explored. In this study, we employ a large number of in-house and publicly available CRISPR, shRNA and drug screens in an effort to characterize the genetic dependencies of 1q-amplified myeloma and discover drugs that target them. Ultimately, we hope to propose a tailored therapeutic strategy for patients with 1q-amplified multiple myeloma. Methods To assess the genetic dependencies of 1q-amplified myeloma, we performed an shRNA screen in multiple myeloma cell lines, targeting genes in the 1q21-1q23 region. Corresponding C911 hairpins were designed for every target shRNA, and DEMETER2 was used to infer on-target effect. To that same end, we analyzed publicly available dependency data from Project Achilles (Whole-genome CRISPR screen, Avana library, 18Q4 release) and Dependency Map (combined RNAi dataset, accessed on 6/20/2018) and looked for differential dependencies in 1q-amplified multiple myeloma cell lines. Different sets of 1q-amplified and non-amplified cell lines were included in each dataset to avoid cell line-specific effects. Genes that both constituted differential dependencies and were differentially expressed were considered as hits. GSEA was used for pathway analysis. To assess differential sensitivity of 1q-amplified myeloma to drugs, we performed a drug screen utilizing the Broad Institute's Drug Repurposing Library-a library of over 5,000 drugs that have cleared varied stages of clinical testing, and compared normalized viability values between 1q-amplified and non-amplified myeloma cell lines. Utilizing publicly available patient data, we also built a 1q-amplification gene expression signature and used it to query the Connectivity Map (CMap) database. Drugs that were predicted to reverse our signature were then used in a new drug screen of myeloma cell lines. Results Through multiple dependency screens, we identified a total of 206 differential dependencies in 1q-amplified myeloma. Out of those, 46 came up in two screens (double hits), while 4 came up in all three datasets (triple hits). CLK-2, a serine/threonine and tyrosine kinase involved in mRNA splicing and POLR3C, a gene encoding a subunit of RNA-polymerase III, were among the triple hits. MCL-1, UBQLN4, CERS2, JTB, BCL9 and PEX19 were among the double hits. With at least four members affected (UBQLN4, UBE2Q1, UBAP2L and UBE2T), the ubiquitin pathway came up as an important differential dependency, while GSEA identified cell cycle as another pathway of essentiality in 1q-amplified multiple myeloma. Next, we searched for differential drug sensitivities utilizing the Drug Repurposing Library as well as a CMap-guided screen, as described above. We identified as hits several compounds targeting the MDM2 ubiquitin ligase as well as compounds related to cell cycle control, including PARP inhibitors and chemotherapeutic agents like fludarabine, thus validating the dependencies discovered in our datasets. Conclusion We employed a combination of multiple in-house and publicly available CRISPR, shRNA and drug screens, in the largest to date effort to characterize and target the genetic dependencies of 1q-amplified multiple myeloma. Cell cycle and the ubiquitin pathway came up as strong dependencies, while the drugs that target them were indeed shown to preferentially kill 1q-amplified myeloma cell lines. Thus, for the first time, our results suggest that patients with 1q-amplified myeloma might benefit from genetically tailored treatment involving cell cycle and ubiquitin inhibitors or a combination thereof. And inasmuch as 1q amplification is one of myeloma's few frequent alterations, this discovery has the exciting potential to affect change in a large number of patients. Disclosures Leleu: BMS: Honoraria, Other: steering committee membership ; Janssen: Honoraria, Other; Merk: Honoraria, Other: steering committee membership ; Takeda: Honoraria, Other: steering committee membership ; Amgen: Honoraria, Other: steering committee membership ; Sanofi: Honoraria, Other: steering committee membership steering committee membership ; Novartis: Honoraria, Other: steering committee membership ; Roche: Honoraria; Gilead: Honoraria; Incyte: Honoraria, Other: steering committee membership ; Karyopharm: Honoraria; Celgene: Honoraria, Other: steering committee membership . Ghobrial:Takeda: Consultancy; Janssen: Consultancy; Celgene: Consultancy; BMS: Consultancy.

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Poskus, Edgardo. "LABORATORIO DE INMUNOENDOCRINOLOGÍA." Revista de la Sociedad Argentina de Diabetes 51, no. 2 (July 24, 2018): 34. http://dx.doi.org/10.47196/diab.v51i2.67.

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El Laboratorio de Inmunoendocrinología (LIE) funciona en la Cátedra de Inmunología de la Facultad de Farmacia y Bioquímica (FFyB) de la Universidad de Buenos Aires (UBA) e Instituto de Estudios de la Inmunidad Humoral Prof. Ricardo A Margni (IDEHU), CONICET-UBA.El líder natural del LIE es el Dr. Edgardo Poskus, quien actualmente se desempeña como Profesor Consulto de la UBA e Investigador Contratado de CONICET.

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Bai, Dou-Sheng, Chao Wu, Liu-Xiao Yang, Chi Zhang, Peng-Fei Zhang, Yi-Zhou He, Jia-Bin Cai, et al. "UBAP2 negatively regulates the invasion of hepatocellular carcinoma cell by ubiquitinating and degradating Annexin A2." Oncotarget 7, no. 22 (April 18, 2016): 32946–55. http://dx.doi.org/10.18632/oncotarget.8783.

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Zhang, Hao, Guangchao Wang, Chen Ding, Peng Liu, Renkai Wang, Wenbin Ding, Dake Tong, et al. "Increased circular RNA UBAP2 acts as a sponge of miR-143 to promote osteosarcoma progression." Oncotarget 8, no. 37 (June 27, 2017): 61687–97. http://dx.doi.org/10.18632/oncotarget.18671.

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Rastogi, V. K., E. S. P. Bromfield, S. T. Whitwill, and L. R. Barran. "A cryptic plasmid of indigenous Rhizobium meliloti possesses reiterated nodC and nifE genes and undergoes DNA rearrangement." Canadian Journal of Microbiology 38, no. 6 (June 1, 1992): 563–68. http://dx.doi.org/10.1139/m92-092.

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Indigenous Rhizobium meliloti were previously characterized on the basis of plasmid profiles and phage sensitivity patterns (phage types). Rhizobium meliloti 1076, which contained two cryptic plasmids, was one of four isolates comprising phage type 23. In this study, the large cryptic plasmid pVS1(size >500 b) was transferred from isolate 1076 into the plasmid-free strain of Agrobacterium tumefaciens UBAPF1. This plasmid contained nucleotide sequences homologous to genes for nodulation (nodB, nodC) and nitrogen fixation (nifH, nifD, nifK, nifE). Cosmid clones possessing the nod and nif homologous sequences, which had been selected from a genomic bank of A. tumefaciens UBAPF1 containing pVS1, complemented R. meliloti nodC and nifE mutants, respectively. These results demonstrate that the nodC and nifE homologous sequences are functionally expressed. Three of four isolates comprising phage type 23 possessed a megaplasmid band in agarose gels characteristic of R. meliloti, as well as two cryptic plasmids. The fourth isolate (No. 323) lacked the large cryptic plasmid corresponding to pVS1, but instead showed a band of lesser mobility than that of the megaplasmids. Nevertheless, its restricted genomic DNA retained the nodC and nifE hybridizing fragments characteristic of pVS1, indicating that the cryptic plasmid has undergone DNA rearrangement. Key words: Rhizobium, plasmid, reiteration, genes, rearrangement.

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Moutty, Marie Christine, Volkan Sakin, and Frauke Melchior. "Importin α/β mediates nuclear import of individual SUMO E1 subunits and of the holo-enzyme." Molecular Biology of the Cell 22, no. 5 (March 2011): 652–60. http://dx.doi.org/10.1091/mbc.e10-05-0461.

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SUMOylation, reversible attachment of small ubiquitin-related modifier (SUMO), serves to regulate hundreds of proteins. Consistent with predominantly nuclear targets, enzymes required for attachment and removal of SUMO are highly enriched in this compartment. This is true also for the first enzyme of the SUMOylation cascade, the SUMO E1 enzyme heterodimer, Aos1/Uba2 (SAE1/SAE2). This essential enzyme serves to activate SUMO and to transfer it to the E2-conjugating enzyme Ubc9. Although the last 40 amino acids in yeast Uba2 have been implicated in its nuclear localization, little was known about the import pathways of Aos1, Uba2, and/or of the assembled E1 heterodimer. Here we show that the mammalian E1 subunits can be imported separately, identify nuclear localization signals (NLSs) in Aos1 and in Uba2, and demonstrate that their import is mediated by importin α/β in vitro and in intact cells. Once assembled into a stable heterodimer, the E1 enzyme can still be efficiently imported by importin α/β, due to the Uba2 NLS that is still accessible. These pathways may serve distinct purposes: import of nascent subunits prior to assembly and reimport of stable E1 enzyme complex after mitosis.

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Bourinaris, Thomas, Damian Smedley, Valentina Cipriani, Isabella Sheikh, Alkyoni Athanasiou-Fragkouli, Patrick Chinnery, Huw Morris, et al. "Identification of UBAP1 mutations in juvenile hereditary spastic paraplegia in the 100,000 Genomes Project." European Journal of Human Genetics 28, no. 12 (September 15, 2020): 1763–68. http://dx.doi.org/10.1038/s41431-020-00720-w.

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AbstractHereditary spastic paraplegia (HSP) is a group of heterogeneous inherited degenerative disorders characterized by lower limb spasticity. Fifty percent of HSP patients remain yet genetically undiagnosed. The 100,000 Genomes Project (100KGP) is a large UK-wide initiative to provide genetic diagnosis to previously undiagnosed patients and families with rare conditions. Over 400 HSP families were recruited to the 100KGP. In order to obtain genetic diagnoses, gene-based burden testing was carried out for rare, predicted pathogenic variants using candidate variants from the Exomiser analysis of the genome sequencing data. A significant gene-disease association was identified for UBAP1 and HSP. Three protein truncating variants were identified in 13 patients from 7 families. All patients presented with juvenile form of pure HSP, with median age at onset 10 years, showing autosomal dominant inheritance or de novo occurrence. Additional clinical features included parkinsonism and learning difficulties, but their association with UBAP1 needs to be established.

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Pashkova, Natasha, and Robert C. Piper. "UBAP1: A New ESCRT Member Joins the cl_Ub." Structure 20, no. 3 (March 2012): 383–85. http://dx.doi.org/10.1016/j.str.2012.02.004.

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Farazi Fard, Mohammad Ali, Adriana P. Rebelo, Elena Buglo, Hamid Nemati, Hassan Dastsooz, Ina Gehweiler, Selina Reich, et al. "Truncating Mutations in UBAP1 Cause Hereditary Spastic Paraplegia." American Journal of Human Genetics 104, no. 6 (June 2019): 1251. http://dx.doi.org/10.1016/j.ajhg.2019.05.009.

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Farazi Fard, Mohammad Ali, Adriana P. Rebelo, Elena Buglo, Hamid Nemati, Hassan Dastsooz, Ina Gehweiler, Selina Reich, et al. "Truncating Mutations in UBAP1 Cause Hereditary Spastic Paraplegia." American Journal of Human Genetics 104, no. 4 (April 2019): 767–73. http://dx.doi.org/10.1016/j.ajhg.2019.03.001.

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Guo, Huaqun, Yongdong Wu, Feng Bao, Hongmei Chen, and Maode Ma. "UBAPV2G: A Unique Batch Authentication Protocol for Vehicle-to-Grid Communications." IEEE Transactions on Smart Grid 2, no. 4 (December 2011): 707–14. http://dx.doi.org/10.1109/tsg.2011.2168243.

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Matsuda, Atsushi, and James D. Forney. "The SUMO Pathway Is Developmentally Regulated and Required for Programmed DNA Elimination in Paramecium tetraurelia." Eukaryotic Cell 5, no. 5 (May 2006): 806–15. http://dx.doi.org/10.1128/ec.5.5.806-815.2006.

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ABSTRACT Extensive genome-wide remodeling occurs during the formation of the somatic macronuclei from the germ line micronuclei in ciliated protozoa. This process is limited to sexual reproduction and includes DNA amplification, chromosome fragmentation, and the elimination of internal segments of DNA. Our efforts to define the pathways regulating these events revealed a gene encoding a homologue of ubiquitin activating enzyme 2 (UBA2) that is upregulated at the onset of macronuclear development in Paramecium tetraurelia. Uba2 enzymes are known to activate the protein called small ubiquitin-related modifier (SUMO) that is covalently attached to target proteins. Consistent with this relationship, Northern analysis showed increased abundance of SUMO transcripts during sexual reproduction in Paramecium. RNA interference (RNAi) against UBA2 or SUMO during vegetative growth had little effect on cell survival or fission rates. In contrast, RNAi of mating cells resulted in failure to form a functional macronucleus. Despite normal amplification of the genome, excision of internal eliminated sequences was completely blocked. Additional experiments showed that the homologous UBA2 and SUMO genes in Tetrahymena thermophila are also upregulated during conjugation. These results provide evidence for the developmental regulation of the SUMO pathway in ciliates and suggest a key role for the pathway in controlling genome remodeling.

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Bakr, M. E., M. Nagy, and Abdulhakim A. Al-Babtain. "Non-parametric hypothesis testing to model some cancers based on goodness of fit." AIMS Mathematics 7, no. 8 (2022): 13733–45. http://dx.doi.org/10.3934/math.2022756.

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<abstract> <p>By observing the failure behavior of the recorded survival data, we aim to compare the different processing approaches or the effectiveness of the devices or systems applied in this non-parametric statistical test. We'll apply the proposed strategy of used better than aged in Laplace (UBAL) transform order, which assumes that the data used in the test will either behave as UBAL Property or exponential behavior. If the survival data is UBAL, it means that the suggested treatment strategy is effective, whereas if the data is exponential, the recommended treatment strategy has no negative or positive effect on patients, as indicated in the application section. To guarantee the test's validity, we calculated the suggested test's power in both censored and uncensored data, as well as its efficiency, compared the results to other tests, and then applied the test to a variety of real data.</p> </abstract>

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Shaeffer, Joseph R., and Robert E. Cohen. "Ubiquitin Aldehyde Increases Adenosine Triphosphate–Dependent Proteolysis of Hemoglobin α-Subunits in β-Thalassemic Hemolysates." Blood 90, no. 3 (August 1, 1997): 1300–1308. http://dx.doi.org/10.1182/blood.v90.3.1300.

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Abstract Two major causes of the anemia in β-thalassemia are a deficiency in hemoglobin (Hb) β-subunit (and consequently HbA) synthesis and, due to the resulting excess of Hb α-subunits, erythroid cell hemolysis. The hemolytic component might be ameliorated by increasing the intracellular proteolysis of the excess α-subunits. Isolated 3H-labeled α-chains are known to be degraded primarily by the adenosine triphosphate (ATP)- and ubiquitin (Ub)-dependent proteolysis pathway in unfractionated β-thalassemic hemolysates. Our objective was to increase this degradation by targeted intervention. Ub aldehyde (Ubal), a synthetic inhibitor of isopeptidases (proteases that hydrolyze the bond between the Ub polypeptide and its protein adduct), was added to reaction mixtures containing a hemolysate from the blood cells of one of four β-thalassemic donors and 3H-α-chains or 3H-α-globin as a substrate. Optimum enhancement of ATP-dependent degradation occurred at 0.4 to 1.5 μmol/L Ubal and ranged from 29% to 115% for 3H-α-chains and 47% to 96% for 3H-α-globin among the four hemolysates. We suggest that Ubal stimulates 3H-α-subunit proteolysis by inhibition of an isopeptidase(s) that deubiquitinates, or “edits,” Ub-3H-α-subunit conjugates, intermediates in the degradative pathway. In control studies, similarly low Ubal concentrations did not enhance the degradation of 3H-α2β2 (HbA) tetramers or inhibit the activities of methemoglobin reductase and four selected glycolysis pathway enzymes. These and other results may be the basis for a therapeutic approach to β-thalassemia.

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Shaeffer, Joseph R., and Robert E. Cohen. "Ubiquitin Aldehyde Increases Adenosine Triphosphate–Dependent Proteolysis of Hemoglobin α-Subunits in β-Thalassemic Hemolysates." Blood 90, no. 3 (August 1, 1997): 1300–1308. http://dx.doi.org/10.1182/blood.v90.3.1300.1300_1300_1308.

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Two major causes of the anemia in β-thalassemia are a deficiency in hemoglobin (Hb) β-subunit (and consequently HbA) synthesis and, due to the resulting excess of Hb α-subunits, erythroid cell hemolysis. The hemolytic component might be ameliorated by increasing the intracellular proteolysis of the excess α-subunits. Isolated 3H-labeled α-chains are known to be degraded primarily by the adenosine triphosphate (ATP)- and ubiquitin (Ub)-dependent proteolysis pathway in unfractionated β-thalassemic hemolysates. Our objective was to increase this degradation by targeted intervention. Ub aldehyde (Ubal), a synthetic inhibitor of isopeptidases (proteases that hydrolyze the bond between the Ub polypeptide and its protein adduct), was added to reaction mixtures containing a hemolysate from the blood cells of one of four β-thalassemic donors and 3H-α-chains or 3H-α-globin as a substrate. Optimum enhancement of ATP-dependent degradation occurred at 0.4 to 1.5 μmol/L Ubal and ranged from 29% to 115% for 3H-α-chains and 47% to 96% for 3H-α-globin among the four hemolysates. We suggest that Ubal stimulates 3H-α-subunit proteolysis by inhibition of an isopeptidase(s) that deubiquitinates, or “edits,” Ub-3H-α-subunit conjugates, intermediates in the degradative pathway. In control studies, similarly low Ubal concentrations did not enhance the degradation of 3H-α2β2 (HbA) tetramers or inhibit the activities of methemoglobin reductase and four selected glycolysis pathway enzymes. These and other results may be the basis for a therapeutic approach to β-thalassemia.

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Bang, Benedicte, Jesper Eisfeldt, Gisela Barbany, Arja Harila-Saari, Mats Heyman, Vasilios Zachariadis, Fulya Taylan, and Ann Nordgren. "A somatic UBA2 variant preceded ETV6-RUNX1 in the concordant BCP-ALL of monozygotic twins." Blood Advances 6, no. 7 (April 4, 2022): 2275–89. http://dx.doi.org/10.1182/bloodadvances.2021005703.

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Abstract Genetic analysis of leukemic clones in monozygotic twins with concordant acute lymphoblastic leukemia (ALL) has proved a unique opportunity to gain insight into the molecular phylogenetics of leukemogenesis. Using whole-genome sequencing, we characterized constitutional and somatic single nucleotide variants/insertion-deletions (indels) and structural variants in a monozygotic twin pair with concordant ETV6-RUNX1+ B-cell precursor ALL (BCP-ALL). In addition, digital PCR (dPCR) was applied to evaluate the presence of and quantify selected somatic variants at birth, diagnosis, and remission. A shared somatic complex rearrangement involving chromosomes 11, 12, and 21 with identical fusion sequences in leukemias of both twins offered direct proof of a common clonal origin. The ETV6-RUNX1 fusion detected at diagnosis was found to originate from this complex rearrangement. A shared somatic frameshift deletion in UBA2 was also identified in diagnostic samples. In addition, each leukemia independently acquired analogous deletions of 3 genes recurrently targeted in BCP-ALLs (ETV6, ATF7IP, and RAG1/RAG2), providing evidence of a convergent clonal evolution only explained by a strong concurrent selective pressure. Quantification of the UBA2 deletion by dPCR surprisingly indicated it persisted in remission. This, for the first time to our knowledge, provided evidence of a UBA2 variant preceding the well-established initiating event ETV6-RUNX1. Further, we suggest the UBA2 deletion exerted a leukemia predisposing effect and that its essential role in Small Ubiquitin-like Modifier (SUMO) attachment (SUMOylation), regulating nearly all physiological and pathological cellular processes such as DNA-repair by nonhomologous end joining, may hold a mechanistic explanation for the predisposition.

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Wang, Jianda, Yanqi Hou, Lina Qi, Shuang Zhai, Liangwu Zheng, Lin Han, Yufan Guo, et al. "Autosomal dominant hereditary spastic paraplegia caused by mutation of UBAP1." neurogenetics 21, no. 3 (March 28, 2020): 169–77. http://dx.doi.org/10.1007/s10048-020-00608-3.

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Wu, Yu, Lingran Zhi, Ying Zhao, Lili Yang, and Fengmei Cai. "Knockdown of circular RNA UBAP2 inhibits the malignant behaviours of esophageal squamous cell carcinoma by microRNA‐422a/Rab10 axis." Clinical and Experimental Pharmacology and Physiology 47, no. 7 (February 17, 2020): 1283–90. http://dx.doi.org/10.1111/1440-1681.13269.

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Wang, Jianxin, Tianxiao Li, and Bin Wang. "Circ‐UBAP2 functions as sponges of miR‐1205 and miR‐382 to promote glioma progression by modulating STC1 expression." Cancer Medicine 10, no. 5 (February 5, 2021): 1815–28. http://dx.doi.org/10.1002/cam4.3759.

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Wang, Li, Hongying Zhao, Jing Li, Yingqi Xu, Yujia Lan, Wenkang Yin, Xiaoqin Liu, et al. "Identifying functions and prognostic biomarkers of network motifs marked by diverse chromatin states in human cell lines." Oncogene 39, no. 3 (September 19, 2019): 677–89. http://dx.doi.org/10.1038/s41388-019-1005-1.

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Abstract Epigenetic modifications play critical roles in modulating gene expression, yet their roles in regulatory networks in human cell lines remain poorly characterized. We integrated multiomics data to construct directed regulatory networks with nodes and edges labeled with chromatin states in human cell lines. We observed extensive association of diverse chromatin states and network motifs. The gene expression analysis showed that diverse chromatin states of coherent type-1 feedforward loop (C1-FFL) and incoherent type-1 feedforward loops (I1-FFL) contributed to the dynamic expression patterns of targets. Notably, diverse chromatin state compositions could help C1- or I1-FFL to control a large number of distinct biological functions in human cell lines, such as four different types of chromatin state compositions cooperating with K562-associated C1-FFLs controlling “regulation of cytokinesis,” “G1/S transition of mitotic cell cycle,” “DNA recombination,” and “telomere maintenance,” respectively. Remarkably, we identified six chromatin state-marked C1-FFL instances (HCFC1-NFYA-ABL1, THAP1-USF1-BRCA2, ZNF263-USF1-UBA52, MYC-ATF1-UBA52, ELK1-EGR1-CCT4, and YY1-EGR1-INO80C) could act as prognostic biomarkers of acute myelogenous leukemia though influencing cancer-related biological functions, such as cell proliferation, telomere maintenance, and DNA recombination. Our results will provide novel insight for better understanding of chromatin state-mediated gene regulation and facilitate the identification of novel diagnostic and therapeutic biomarkers of human cancers.

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Legge, S. E., M. L. Hamshere, S. Ripke, A. F. Pardinas, J. I. Goldstein, E. Rees, A. L. Richards, et al. "Genome-wide common and rare variant analysis provides novel insights into clozapine-associated neutropenia." Molecular Psychiatry 22, no. 10 (July 12, 2016): 1502–8. http://dx.doi.org/10.1038/mp.2016.97.

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Abstract The antipsychotic clozapine is uniquely effective in the management of schizophrenia; however, its use is limited by its potential to induce agranulocytosis. The causes of this, and of its precursor neutropenia, are largely unknown, although genetic factors have an important role. We sought risk alleles for clozapine-associated neutropenia in a sample of 66 cases and 5583 clozapine-treated controls, through a genome-wide association study (GWAS), imputed human leukocyte antigen (HLA) alleles, exome array and copy-number variation (CNV) analyses. We then combined associated variants in a meta-analysis with data from the Clozapine-Induced Agranulocytosis Consortium (up to 163 cases and 7970 controls). In the largest combined sample to date, we identified a novel association with rs149104283 (odds ratio (OR)=4.32, P=1.79 × 10−8), intronic to transcripts of SLCO1B3 and SLCO1B7, members of a family of hepatic transporter genes previously implicated in adverse drug reactions including simvastatin-induced myopathy and docetaxel-induced neutropenia. Exome array analysis identified gene-wide associations of uncommon non-synonymous variants within UBAP2 and STARD9. We additionally provide independent replication of a previously identified variant in HLA-DQB1 (OR=15.6, P=0.015, positive predictive value=35.1%). These results implicate biological pathways through which clozapine may act to cause this serious adverse effect.

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Wang, Shengting, Qian Li, Yufang Wang, Xiaoming Li, Rui Wang, Yuhua Kang, Xukai Xue, Rui Meng, Qi Wei, and Xinghua Feng. "Upregulation of circ-UBAP2 predicts poor prognosis and promotes triple-negative breast cancer progression through the miR-661/MTA1 pathway." Biochemical and Biophysical Research Communications 505, no. 4 (November 2018): 996–1002. http://dx.doi.org/10.1016/j.bbrc.2018.10.026.

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Rollinson, Sara J., Stephen K. Sikkink, Nicola A. Halliwell, Patrizia Rizzu Rizzu, Peter Heutink, John Van Swieten, David Mann, and Stuart Pickering-Brown. "P2-106: UBAP1 is a risk factor for frontotemporal lobar degeneration." Alzheimer's & Dementia 4 (July 2008): T402. http://dx.doi.org/10.1016/j.jalz.2008.05.1180.

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Lloyd, S. Julie-Ann, Sumana Raychaudhuri, and Peter J. Espenshade. "Subunit Architecture of the Golgi Dsc E3 Ligase Required for Sterol Regulatory Element-binding Protein (SREBP) Cleavage in Fission Yeast." Journal of Biological Chemistry 288, no. 29 (June 12, 2013): 21043–54. http://dx.doi.org/10.1074/jbc.m113.468215.

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Abstract:

The membrane-bound sterol regulatory element-binding protein (SREBP) transcription factors regulate lipogenesis in mammalian cells and are activated through sequential cleavage by the Golgi-localized Site-1 and Site-2 proteases. The mechanism of fission yeast SREBP cleavage is less well defined and, in contrast, requires the Golgi-localized Dsc E3 ligase complex. The Dsc E3 ligase consists of five integral membrane subunits, Dsc1 through Dsc5, and resembles membrane E3 ligases that function in endoplasmic reticulum-associated degradation. Using immunoprecipitation assays and blue native electrophoresis, we determined the subunit architecture for the complex of Dsc1 through Dsc5, showing that the Dsc proteins form subcomplexes and display defined connectivity. Dsc2 is a rhomboid pseudoprotease family member homologous to mammalian UBAC2 and a central component of the Dsc E3 ligase. We identified conservation in the architecture of the Dsc E3 ligase and the multisubunit E3 ligase gp78 in mammals. Specifically, Dsc1-Dsc2-Dsc5 forms a complex resembling gp78-UBAC2-UBXD8. Further characterization of Dsc2 revealed that its C-terminal UBA domain can bind to ubiquitin chains but that the Dsc2 UBA domain is not essential for yeast SREBP cleavage. Based on the ability of rhomboid superfamily members to bind transmembrane proteins, we speculate that Dsc2 functions in SREBP recognition and binding. Homologs of Dsc1 through Dsc4 are required for SREBP cleavage and virulence in the human opportunistic pathogen Aspergillus fumigatus. Thus, these studies advance our organizational understanding of multisubunit E3 ligases involved in endoplasmic reticulum-associated degradation and fungal pathogenesis.

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Qina, Jun, Ke Tang, Li Cao, Wei-fang Li, Rong Wang, and Gui-yuan Li. "In silico expression analysis of human novel gene UBAP1 in multiple cancers." Chinese Journal of Cancer Research 14, no. 3 (September 2002): 157–60. http://dx.doi.org/10.1007/s11670-002-0035-2.

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