U2AF35(S34F) Promotes Transformation by Directing Aberrant ATG7 Pre-mRNA 3′ End Formation

Park, Sung Mi; Ou, Jianhong; Chamberlain, Lynn; Simone, Tessa M.; Yang, Huan; Virbasius, Ching-Man A.; Ali, Abdullah Mahmood; Zhu, Lihua Julie; Mukherjee, Siddhartha; Raza, Azra; Green, Michael R.

doi:10.1016/j.molcel.2016.04.011

Cited by 114 publications

(143 citation statements)

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“…In contrast, several recent studies have identified that ablation of the mutant RNA splicing factor allele appears to have no effect on cancer maintenance. 11,25,44 This was demonstrated in 2 studies where deletion of the mutant U2AF1 S34F or SF3B1 …”

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confidence: 91%

“…8, [23][24][25] Although there have been major advances in understanding the role of RNA splicing factor mutations in MDS pathogenesis and therapy (as reviewed recently [26][27][28] ), major questions about their biological consequences within cells, requirement in disease initiation vs maintenance, and cell autonomous vs nonautonomous roles remain. In addition, numerous questions about the structural and biochemical effects of the mutations on protein-protein and protein-RNA interactions.…”

Section: Introductionmentioning

confidence: 99%

“…25 In this study, the authors identified that overexpression of mutant U2AF1 S34F is capable of transforming cytokine-dependent Ba/F3 cells. However, once transformed, the cells no longer required the mutant RNA splicing factor for cytokine-independent growth.…”

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confidence: 96%

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How do messenger RNA splicing alterations drive myelodysplasia?

Joshi

Halene

Abdel-Wahab

2017

Blood

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Mutations in RNA splicing factors are the single most common class of genetic alterations in myelodysplastic syndrome (MDS) patients. Although much has been learned about how these mutations affect splicing at a global-and transcript-specific level, critical questions about the role of these mutations in MDS development and maintenance remain. Here we present the questions to be addressed in order to understand the unique enrichment of these mutations in MDS. (Blood. 2017; 129(18):2465-2470 IntroductionMyelodysplastic syndromes (MDSs) represent clonal disorders of hematopoietic stem cells (HSCs) whereby hematopoietic cell-intrinsic genetic alterations as well as non-cell autonomous factors contribute to an aberrant HSC that produces morphologically abnormal progeny and has impaired ability to generate mature blood cells. Due to the wide clinical and morphologic heterogeneity of MDS, substantial effort has been placed on characterizing the genetic alterations present in MDS cells in hopes of improving our ability to understand, diagnose, and treat the disease. Extensive targeted mutational analysis of protein coding genes has identified that MDS is characterized by a high frequency of mutations in genes encoding messenger RNA (mRNA) splicing factors as well as epigenetic modifiers.1-3 The discovery of mutations in RNA splicing factors in particular was quite unexpected as these mutations are generally uncommon in cancer yet are present in 50% to 60% of MDS patients. Interestingly, there are clear associations between specific mutated splicing factors and subtypes of MDS, most notably mutations in the RNA splicing factor SF3B1 in .90% of patients with MDS with ring sideroblasts.1,2,4 Moreover, the nature of these mutations is quite conspicuous as they occur as heterozygous point mutations at highly recurrent residues. Finally, within MDS patients, these mutations are almost always mutually exclusive; an MDS patient almost never has .1 RNA splicing factor mutation at the same time [1][2][3] (although rare individuals with mutations in .1 RNA splicing factor have been noted, 5 these occur far less frequently than expected by chance in MDS and it is unclear if both mutations in such cases are present within the same cell and/or how the mutations may impact splicing if coexpressed in the same cell).The discovery of RNA splicing factor mutations has led to intense efforts to understand their biological impact on hematopoiesis, 6-9 their genomic and biochemical effects on RNA splicing, 10-21 their structural effects, 22 and potential means to therapeutically target cells bearing these mutations. 8,[23][24][25] Although there have been major advances in understanding the role of RNA splicing factor mutations in MDS pathogenesis and therapy (as reviewed recently [26][27][28] ), major questions about their biological consequences within cells, requirement in disease initiation vs maintenance, and cell autonomous vs nonautonomous roles remain. In addition, numerous questions about the structural and biochemical effects of...

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confidence: 91%

Section: Introductionmentioning

confidence: 99%

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How do messenger RNA splicing alterations drive myelodysplasia?

Joshi

Halene

Abdel-Wahab

2017

Blood

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“…58 In addition, a recent study demonstrated that ectopic expression of S34F U2AF1 in Ba/F3 cells resulted in increased use of distal mRNA cleavage and polyadenylation sites. 66 One of the affected transcripts was Atg7, which led to reduced protein levels and a functional autophagy defect.Deep sequencing analysis of U2AF1 mutant patient samples, transgenic mice, and isogenic cell lines have demonstrated the presence of global changes that affect 5% to 10% of the transcriptome.52,57 Some of these recurrent alternatively spliced genes are implicated in essential cellular processes, such us RNA processing and splicing, protein translation, DNA methylation, and DNA damage response and apoptosis, and can also occur in genes that are recurrently mutated in MDS. 52,57,58,63,64,67 However, the functional contribution to the disease phenotype of alternatively spliced genes remains an active area of research.…”

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confidence: 99%

Splicing factor gene mutations in hematologic malignancies

Sáez

Walter

Graubert

2017

Blood

108

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Alternative splicing generates a diversity of messenger RNA (mRNA) transcripts from a single mRNA precursor and contributes to the complexity of our proteome. Splicing is perturbed by a variety of mechanisms in cancer. Recurrent mutations in splicing factors have emerged as a hallmark of several hematologic malignancies. Splicing factor mutations tend to occur in the founding clone of myeloid cancers, and these mutations have recently been identified in blood cells from normal, healthy elderly individuals with clonal hematopoiesis who are at increased risk of subsequently developing a hematopoietic malignancy, suggesting that these mutations contribute to disease initiation. Splicing factor mutations change the pattern of splicing in primary patient and mouse hematopoietic cells and alter hematopoietic differentiation and maturation in animal models. Recent developments in this field are reviewed here, with an emphasis on the clinical consequences of splicing factor mutations, mechanistic insights from animal models, and implications for development of novel therapies targeting the precursor mRNA splicing pathway. (Blood. 2017;129(10):1260-1269 IntroductionThe control of messenger RNA (mRNA) processing is a crucial component of gene regulation. The precursor messenger RNA (premRNA) sequence contains exons that flank introns, which are removed during splicing.1 Human genes are remarkably complex, containing an average of 8 exons, with introns composing up to 90% of the pre-mRNA sequence.2,3 Up to 94% of human genes generate multiple mRNA isoforms. [4][5][6] The spliceosome is a multiprotein complex consisting of 5 small nuclear ribonucleoproteins (snRNPs) and more than 150 proteins that recognizes the elements near intron-exon boundaries and the branch site that catalyzes the excision of intronic regions. Additional trans-acting factors including SR proteins bind the cis-regulatory sequences (exonic and intronic silencers and enhancers) to promote or prevent spliceosome assembly. [7][8][9] The complexity of regulatory elements that control proper splicing makes this process not only critical to maintain tissue homeostasis, but also highly susceptible to hereditary and somatic mutations that are involved in disease. This review will discuss the implications of aberrant splicing on human disease, with a focus on the impact of somatic mutations in trans-acting splicing factors in hematologic malignancies. Splicing and diseaseA comprehensive analysis of The Cancer Genome Atlas (TCGA) project RNA sequencing (RNA-seq) data from 16 tumor types and matched normal tissue revealed evidence of global alternative splicing involving a variety of splicing junctions, including cassette exons, retrained introns, and competing 59 and 39 splice sites (SSs). 10 In particular, acute myeloid leukemia (AML) cells showed the largest number of alternative spliced events among tumor types.10 Recent evidence from analysis of paired DNA and RNA-seq data from TCGA has shown that somatic mutations affecting splicing regulatory sequences (sp...

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“…Park et al, show that the U2AF35 mutant promoted the usage of a distal poly(A) site in Atg7 mRNA, thus generating a longer, inefficiently translated transcript. Decreased ATG7 led to mitochondrial dysfunction including genomic instability, which induces cells to acquire secondary mutations disposing them to transformation [53] .…”

Section: Hnrnp P2mentioning

confidence: 99%

RNA Processing and Ribosome Biogenesis in Bone Marrow Failure Disorders

Blalock

Piazzi

Gallo

et al. 2017

RNA Dis

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Bone marrow failure disorders (BMFDs), which are characterized by an early pro-apoptotic phase which results in faulty hematopoiesis and anemia, more often than not progress to outright acute myelogenous leukemia (AML). Recent findings have indicated that most if not all of these disorders have a very significant RNA processing component to their pathology. This review aims to highlight some of normal processes of RNA metabolism that have been recently demonstrated to be altered in BMFDs.

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U2AF35(S34F) Promotes Transformation by Directing Aberrant ATG7 Pre-mRNA 3′ End Formation

Cited by 114 publications

References 55 publications

How do messenger RNA splicing alterations drive myelodysplasia?

How do messenger RNA splicing alterations drive myelodysplasia?

Splicing factor gene mutations in hematologic malignancies

RNA Processing and Ribosome Biogenesis in Bone Marrow Failure Disorders

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