Splicing Factor Mutations in Myelodysplasias: Insights from Spliceosome Structures

Jenkins, Jermaine L.; Kielkopf, Clara L.

doi:10.1016/j.tig.2017.03.001

Cited by 60 publications

(72 citation statements)

References 116 publications

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“…This, along with studies that advance a more detailed mechanistic understanding of the splicing process[35, 62] at both the single-gene and genome-wide levels, are key to advancing SPLMs into the clinic. [63]…”

Section: Resultsmentioning

confidence: 99%

A Challenging Pie to Splice: Drugging the Spliceosome

et al. 2017

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Since its discovery in 1977, the study of alternative RNA splicing has revealed a plethora of mechanisms that had never before been documented in nature. Understanding these transitions and their outcome at the level of the cell and organism has become one of the great frontiers of modern chemical biology. Until 2007, this field remained in the hands of RNA biologists. However, the recent identification of natural product and synthetic modulators of RNA splicing has opened new access to this field, allowing for the first time a chemical-based interrogation of RNA splicing processes. Simultaneously, we have begun to understand the vital importance of splicing in disease, which offers a new platform for molecular discovery and therapy. As with many natural systems, gaining clear mechanistic detail at the molecular level is key towards understanding the operation of any biological machine. This minireview presents recent lessons learned in this emerging field of RNA splicing chemistry and chemical biology.

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Section: Resultsmentioning

confidence: 99%

A Challenging Pie to Splice: Drugging the Spliceosome

et al. 2017

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“…Somatic mutations in SF3B1 are frequently found in MDS and chronic lymphocytic leukemia (CLL) patients [50,51]. Studies suggest that mutations in SF3B1 induce malignancy through aberrant transcription, altered pre-mRNA recognition and alternative splicing [50,52]. Similarly, mutations in PRPF8 have been identified in MDS and AML patients where decreased PRPF8 expression is associated with increased exon skipping [53], possibly due to a splicing proofreading defect [53].…”

Section: Ddx41 In Mrna Splicingmentioning

confidence: 99%

Myeloid neoplasms with germline DDX41 mutation

et al. 2017

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to DDX41 mutation and highlights how each of these suggest potential therapeutic opportunities through the use of pathway-specific inhibitors.Keywords DDX41 · Myeloid malignancy · Myelodysplastic syndrome · Acute myeloid leukemia · Germline mutation · Predisposition Familial predisposition to myeloid neoplasmsMyeloid neoplasms are a heterogeneous group of diseases encompassing myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), all of which are characterized by abnormal growth and development of cells of the myeloid blood lineage. These disease groups can be further sub-categorized by a number of different morphological and molecular approaches which may correlate with responses to specific treatments [1]. AML and MDS Abstract Recently, DDX41 mutations have been identified both as germline and acquired somatic mutations in families with multiple cases of late-onset myelodysplastic syndrome (MDS) and/or acute myeloid leukemia. The majority of germline mutations are frameshift mutations suggesting loss of function with DDX41 acting as a tumor suppressor, and there is a common somatic missense mutation found in a majority of germline mutated tumors. Clinically, DDX41 mutations lead to development of high-risk MDS at an age similar to that observed in sporadic cohorts, presenting a unique challenge to hematologists in recognizing the familial context. Functionally, DDX41 has been shown to contribute to multiple pathways and processes including mRNA splicing, innate immunity and rRNA processing. Mutations in DDX41 result in aberrations to each of these in ways that could potentially impact on tumorigenesis-initiation, maintenance or progression. This review discusses the various molecular, clinical and biological aspects of myeloid malignancy predisposition due

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“…1 Previous reports have shown that U2AF65 might be a key regulator of gene expression and related signalling pathway. U2AF65 is encoded by U2AF2 gene, and previous studies have confirmed the central role of U2AF65 in splicing.…”

Section: Discussionmentioning

confidence: 99%

“…1,2 A series of U2AF mutations have been characterized to investigate the functions of U2AF as a splicing factor, and previous studies have revealed that the stoichiometry of U2AF is important for accurate 3′ ss selection. The function of U2AF65 in alternative splicing has been identified; however, the essential physiological role of U2AF65 remains poorly understood.…”

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U2AF65 enhances milk synthesis and growth of bovine mammary epithelial cells by positively regulating the mTOR‐SREBP‐1c signalling pathway

Zhen

et al. 2019

Cell Biochemistry & Function

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U2 snRNP auxiliary factor 65 kDa (U2AF65) is a splicing factor that promotes prespliceosome assembly. The function of U2AF65 in alternative splicing has been identified; however, the essential physiological role of U2AF65 remains poorly understood. In this study, we investigated the regulatory role of U2AF65 in milk synthesis and growth of bovine mammary epithelial cells (BMECs). Our results showed that U2AF65 localizes in the nucleus. Treatment with amino acids (Met and Leu) and hormones (prolactin and β-estradiol) upregulated the expression of U2AF65 in these cells. U2AF65 overexpression increased the synthesis of β-casein, triglycerides, and lactose; increased cell viability; and promoted proliferation of BMECs. Furthermore, our results showed that U2AF65 positively regulated mTOR phosphorylation and expression of mature mRNA of mTOR and SREBP-1c. Collectively, our findings demonstrate that U2AF65 regulates the mRNA expression of signalling molecules (mTOR and SREBP-1c) involved in milk synthesis and growth of BMECs, possibly via controlling the splicing and maturation of these mRNAs. U2 snRNP auxiliary factor 65 kDa (U2AF65) is a splicing factor that promotes prespliceosome assembly. The essential physiological role of U2AF65 remains poorly understood. In the present study, we confirmed that U2AF65 functions as a positive regulator of milk synthesis in and proliferation of bovine mammary epithelial cells via the mTOR-SREBP-1c signalling pathway. Therefore, our study uncovers the regulatory role of U2AF65 in milk synthesis and cell proliferation. KEYWORDS U2AF65, mTOR, SREBP-1c, β-casein, triglyceride, lactose 1 | INTRODUCTION U2 small nuclear ribonucleoprotein (U2snRNP) auxiliary factor (U2AF) is a conserved nuclear factor that plays a crucial role in mRNA splicing. U2AF is a stable heterodimer comprising U2AF65 subunit (65 kDa), which is encoded by U2AF2 gene, and the U2AF35 (35 kDa) subunit, which is encoded by the U2AF1 gene. U2AF65 interacts with the polypyrimidine tract (PPT), a conserved 3′ splice-site (ss) immediately downstream of the branch point sequence (BPS). On the other hand, U2AF35 interacts with invariant AG dinucleotides at the 3′ ss and stabilizes the binding of U2AF65 with RNA. 1,2A series of U2AF mutations have been characterized to investigate the functions of U2AF as a splicing factor, and previous studies have revealed that the stoichiometry of U2AF is important for accurate 3′ ss selection. 3,4 Consistent with the disease phenotype of myelodysplasia, one study indicated that mutations in U2AF cause widespread changes in alternative splicing and is linked to decreased cell proliferation. 5 U2AF has also been reported to be involved in other cellular processes, such as mRNA export, in which it binds to

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Splicing Factor Mutations in Myelodysplasias: Insights from Spliceosome Structures

Cited by 60 publications

References 116 publications

A Challenging Pie to Splice: Drugging the Spliceosome

A Challenging Pie to Splice: Drugging the Spliceosome

Myeloid neoplasms with germline DDX41 mutation

U2AF65 enhances milk synthesis and growth of bovine mammary epithelial cells by positively regulating the mTOR‐SREBP‐1c signalling pathway

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