Mechanistic Insights of Aberrant Splicing with Splicing Factor Mutations Found in Myelodysplastic Syndromes

Pre-mRNA splicing is an essential process for gene expression in higher eukaryotes, which requires a high order of accuracy. Mutations in splicing factors or regulatory elements in pre-mRNAs often result in many human diseases. Myelodysplastic syndrome (MDS) is a heterogeneous group of chronic myeloid neoplasms characterized by many symptoms and a high risk of progression to acute myeloid leukemia. Recent findings indicate that mutations in splicing factors represent a novel class of driver mutations in human cancers and affect about 50% of Myelodysplastic syndrome (MDS) patients. Somatic mutations in MDS patients are frequently found in genes SF3B1, SRSF2, U2AF1, and ZRSR2. Interestingly, they are involved in the recognition of 3′ splice sites and exons. It has been reported that mutations in these splicing regulators result in aberrant splicing of many genes. In this review article, we first describe molecular mechanism of pre-mRNA splicing as an introduction and mainly focus on those four splicing factors to describe their mutations and their associated aberrant splicing patterns.

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Aberrant Bcl-x splicing in cancer: from molecular mechanism to therapeutic modulation

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-02001-w ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Zhihui Dou ◽

Dapeng Zhao ◽

Xiaohua Chen ◽

Caipeng Xu ◽

Xiaodong Jin ◽

...

Keyword(s):

Cancer Cells ◽

Human Cancer ◽

Structural Characteristics ◽

Therapy Resistance ◽

Regulatory Elements ◽

Aberrant Splicing ◽

Clinical Role ◽

Splicing Isoforms ◽

The Impact ◽

Splicing Patterns

AbstractBcl-x pre-mRNA splicing serves as a typical example to study the impact of alternative splicing in the modulation of cell death. Dysregulation of Bcl-x apoptotic isoforms caused by precarious equilibrium splicing is implicated in genesis and development of multiple human diseases, especially cancers. Exploring the mechanism of Bcl-x splicing and regulation has provided insight into the development of drugs that could contribute to sensitivity of cancer cells to death. On this basis, we review the multiple splicing patterns and structural characteristics of Bcl-x. Additionally, we outline the cis-regulatory elements, trans-acting factors as well as epigenetic modifications involved in the splicing regulation of Bcl-x. Furthermore, this review highlights aberrant splicing of Bcl-x involved in apoptosis evade, autophagy, metastasis, and therapy resistance of various cancer cells. Last, emphasis is given to the clinical role of targeting Bcl-x splicing correction in human cancer based on the splice-switching oligonucleotides, small molecular modulators and BH3 mimetics. Thus, it is highlighting significance of aberrant splicing isoforms of Bcl-x as targets for cancer therapy.

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Abstract 3161: Massively parallel transcriptome sequencing in neuroblastoma reveals specific mRNA splicing patterns controlled by RNA binding splicing factors.

10.1158/1538-7445.am2013-3161 ◽

2013 ◽

Author(s):

Shile Zhang ◽

Tom Badgett ◽

Jun Wei ◽

Young K. Song ◽

Dominik Bogen ◽

...

Keyword(s):

Transcriptome Sequencing ◽

Rna Binding ◽

Mrna Splicing ◽

Massively Parallel ◽

Splicing Factors ◽

Splicing Patterns ◽

Specific Mrna

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Organization of transcription and pre-mRNA splicing within the mammalian cell nucleus

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s042482010014021x ◽

1995 ◽

Vol 53 ◽

pp. 768-769

Author(s):

D.L. Spector ◽

S. Huang ◽

S. Kaurin

Keyword(s):

Rna Polymerase Ii ◽

Cell Nucleus ◽

Functional Organization ◽

Mrna Splicing ◽

Splicing Factors ◽

Interchromatin Granule Clusters ◽

Interchromatin Granule ◽

Nuclear Regions ◽

Relationship Of ◽

Perichromatin Fibrils

We have been interested in the organization of RNA polymerase II transcription and pre-mRNA splicing within the cell nucleus. Several models have been proposed for the functional organization of RNA within the eukaryotic nucleus and for the relationship of this organization to the distribution of pre-mRNA splicing factors. One model suggests that RNAs which must be spliced are capable of recruiting splicing factors to the sites of transcription from storage and/or reassembly sites. When one examines the organization of splicing factors in the nucleus in comparison to the sites of chromatin it is clear that splicing factors are not localized in coincidence with heterochromatin (Fig. 1). Instead, they are distributed in a speckled pattern which is composed of both perichromatin fibrils and interchromatin granule clusters. The perichromatin fibrils are distributed on the periphery of heterochromatin and on the periphery of interchromatin granule clusters as well as being diffusely distributed throughout the nucleoplasm. These nuclear regions have been previously shown to represent initial sites of incorporation of 3H-uridine.

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Splicing Genomics Events in Cervical Cancer: Insights for Phenotypic Stratification and Biomarker Potency

Genes ◽

10.3390/genes12020130 ◽

2021 ◽

Vol 12 (2) ◽

pp. 130

Author(s):

Flavia Zita Francies ◽

Sheynaz Bassa ◽

Aristotelis Chatziioannou ◽

Andreas Martin Kaufmann ◽

Zodwa Dlamini

Keyword(s):

Cervical Cancer ◽

Alternative Splicing ◽

Cancer Progression ◽

Molecular Mechanisms ◽

Therapy Resistance ◽

Splicing Factors ◽

Aberrant Splicing ◽

Molecular Alteration ◽

Common Cancer ◽

Potential Biomarkers

Gynaecological cancers are attributed to the second most diagnosed cancers in women after breast cancer. On a global scale, cervical cancer is the fourth most common cancer and the most common cancer in developing countries with rapidly increasing mortality rates. Human papillomavirus (HPV) infection is a major contributor to the disease. HPV infections cause prominent cellular changes including alternative splicing to drive malignant transformation. A fundamental characteristic attributed to cancer is the dysregulation of cellular transcription. Alternative splicing is regulated by several splicing factors and molecular changes in these factors lead to cancer mechanisms such as tumour development and progression and drug resistance. The serine/arginine-rich (SR) proteins and heterogeneous ribonucleoproteins (hnRNPs) have prominent roles in modulating alternative splicing. Evidence shows molecular alteration and expression levels in these splicing factors in cervical cancer. Furthermore, aberrant splicing events in cancer-related genes lead to chemo- and radioresistance. Identifying clinically relevant modifications in alternative splicing events and splicing variants, in cervical cancer, as potential biomarkers for their role in cancer progression and therapy resistance is scrutinised. This review will focus on the molecular mechanisms underlying the aberrant splicing events in cervical cancer that may serve as potential biomarkers for diagnosis, prognosis, and novel drug targets.

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Regulation of RNA Splicing: Aberrant Splicing Regulation and Therapeutic Targets in Cancer

Cells ◽

10.3390/cells10040923 ◽

2021 ◽

Vol 10 (4) ◽

pp. 923

Author(s):

Koji Kitamura ◽

Keisuke Nimura

Keyword(s):

Dna Sequences ◽

Rna Splicing ◽

Splicing Factors ◽

Splicing Regulation ◽

Aberrant Splicing ◽

Aberrant Expression ◽

Non Coding Rnas ◽

Precursor Mrna ◽

Splicing Enhancer ◽

Small Nuclear Ribonucleoproteins

RNA splicing is a critical step in the maturation of precursor mRNA (pre-mRNA) by removing introns and exons. The combination of inclusion and exclusion of introns and exons in pre-mRNA can generate vast diversity in mature mRNA from a limited number of genes. Cancer cells acquire cancer-specific mechanisms through aberrant splicing regulation to acquire resistance to treatment and to promote malignancy. Splicing regulation involves many factors, such as proteins, non-coding RNAs, and DNA sequences at many steps. Thus, the dysregulation of splicing is caused by many factors, including mutations in RNA splicing factors, aberrant expression levels of RNA splicing factors, small nuclear ribonucleoproteins biogenesis, mutations in snRNA, or genomic sequences that are involved in the regulation of splicing, such as 5’ and 3’ splice sites, branch point site, splicing enhancer/silencer, and changes in the chromatin status that affect the splicing profile. This review focuses on the dysregulation of RNA splicing related to cancer and the associated therapeutic methods.

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Negative and Positive mRNA Splicing Elements Act Competitively To Regulate Human Immunodeficiency Virus Type 1 Vif Gene Expression

Journal of Virology ◽

10.1128/jvi.01558-07 ◽

2008 ◽

Vol 82 (8) ◽

pp. 3921-3931 ◽

Cited By ~ 37

Author(s):

C. M. Exline ◽

Z. Feng ◽

C. M. Stoltzfus

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Regulatory Elements ◽

Mrna Splicing ◽

Viral Mrnas ◽

Exon 2 ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT Over 40 different human immunodeficiency virus type 1 (HIV-1) mRNAs are produced by alternative splicing of the primary HIV-1 RNA transcripts. In addition, approximately half of the viral RNA remains unspliced and is used as genomic RNA and as mRNA for the Gag and Pol gene products. Regulation of splicing at the HIV-1 3′ splice sites (3′ss) requires suboptimal polypyrimidine tracts, and positive or negative regulation occurs through the binding of cellular factors to cis-acting splicing regulatory elements. We have previously shown that splicing at HIV-1 3′ss A1, which produces single-spliced vif mRNA and promotes the inclusion of HIV exon 2 into both completely and incompletely spliced viral mRNAs, is increased by optimizing the 5′ splice site (5′ss) downstream of exon 2 (5′ss D2). Here we show that the mutations within 5′ss D2 that are predicted to lower or increase the affinity of the 5′ss for U1 snRNP result in reduced or increased Vif expression, respectively. Splicing at 5′ss D2 was not necessary for the effect of 5′ss D2 on Vif expression. In addition, we have found that mutations of the GGGG motif proximal to the 5′ss D2 increase exon 2 inclusion and Vif expression. Finally, we report the presence of a novel exonic splicing enhancer (ESE) element within the 5′-proximal region of exon 2 that facilitates both exon inclusion and Vif expression. This ESE binds specifically to the cellular SR protein SRp75. Our results suggest that the 5′ss D2, the proximal GGGG silencer, and the ESE act competitively to determine the level of vif mRNA splicing and Vif expression. We propose that these positive and negative splicing elements act together to allow the accumulation of vif mRNA and unspliced HIV-1 mRNA, compatible with optimal virus replication.

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A novel mammalian nuclear protein similar to Schizosaccharomyces pombe Prp1p/Zer1p and Saccharomyces cerevisiae Prp6p pre-mRNA splicing factors

Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology ◽

10.1016/s0167-4838(99)00203-4 ◽

1999 ◽

Vol 1435 (1-2) ◽

pp. 147-152 ◽

Cited By ~ 8

Author(s):

Akihiko Nishikimi ◽

Jiro Mukai ◽

Noriyuki Kioka ◽

Masayasu Yamada

Keyword(s):

Saccharomyces Cerevisiae ◽

Schizosaccharomyces Pombe ◽

Nuclear Protein ◽

Mrna Splicing ◽

Splicing Factors

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Genetic Interactions WithCLF1Identify Additional Pre-mRNA Splicing Factors and a Link Between Activators of Yeast Vesicular Transport and Splicing

Genetics ◽

10.1093/genetics/164.3.895 ◽

2003 ◽

Vol 164 (3) ◽

pp. 895-907 ◽

Cited By ~ 3

Author(s):

Kevin Vincent ◽

Qiang Wang ◽

Steven Jay ◽

Kathryn Hobbs ◽

Brian C Rymond

Keyword(s):

Mrna Splicing ◽

Splicing Factors ◽

Sequence Information ◽

Specific Sequence ◽

Synthetic Lethal ◽

Growth Defects ◽

Mrna Maturation ◽

Assembly Factor ◽

Gtpase Activation ◽

Synthetic Growth

AbstractClf1 is a conserved spliceosome assembly factor composed predominately of TPR repeats. Here we show that the TPR elements are not functionally equivalent, with the amino terminus of Clf1 being especially sensitive to change. Deletion and add-back experiments reveal that the splicing defect associated with TPR removal results from the loss of TPR-specific sequence information. Twelve mutants were found that show synthetic growth defects when combined with an allele that lacks TPR2 (i.e., clf1Δ2). The identified genes encode the Mud2, Ntc20, Prp16, Prp17, Prp19, Prp22, and Syf2 splicing factors and four proteins without established contribution to splicing (Bud13, Cet1, Cwc2, and Rds3). Each synthetic lethal with clf1Δ2 (slc) mutant is splicing defective in a wild-type CLF1 background. In addition to the splicing factors, SSD1, BTS1, and BET4 were identified as dosage suppressors of clf1Δ2 or selected slc mutants. These results support Clf1 function through multiple stages of the spliceosome cycle, identify additional genes that promote cellular mRNA maturation, and reveal a link between Rab/Ras GTPase activation and the process of pre-mRNA splicing.

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A Functional Interaction between the Carboxy-Terminal Domain of RNA Polymerase II and Pre-mRNA Splicing

The Journal of Cell Biology ◽

10.1083/jcb.136.1.5 ◽

1997 ◽

Vol 136 (1) ◽

pp. 5-18 ◽

Cited By ~ 91

Author(s):

Lei Du ◽

Stephen L. Warren

Keyword(s):

Rna Polymerase Ii ◽

Mammalian Cells ◽

Mrna Splicing ◽

Splicing Factors ◽

Functional Interaction ◽

Carboxy Terminal Domain ◽

Localization Signal ◽

Nuclear Domains ◽

Carboxy Terminal

In the preceding study we found that Sm snRNPs and SerArg (SR) family proteins co-immunoprecipitate with Pol II molecules containing a hyperphosphorylated CTD (Kim et al., 1997). The association between Pol IIo and splicing factors is maintained in the absence of pre-mRNA, and the polymerase need not be transcriptionally engaged (Kim et al., 1997). The latter findings led us to hypothesize that a phosphorylated form of the CTD interacts with pre-mRNA splicing components in vivo. To test this idea, a nested set of CTD-derived proteins was assayed for the ability to alter the nuclear distribution of splicing factors, and to interfere with splicing in vivo. Proteins containing heptapeptides 1-52 (CTD52), 1-32 (CTD32), 1-26 (CTD26), 1-13 (CTD13), 1-6 (CTD6), 1-3 (CTD3), or 1 (CTD1) were expressed in mammalian cells. The CTD-derived proteins become phosphorylated in vivo, and accumulate in the nucleus even though they lack a conventional nuclear localization signal. CTD52 induces a selective reorganization of splicing factors from discrete nuclear domains to the diffuse nucleoplasm, and significantly, it blocks the accumulation of spliced, but not unspliced, human β-globin transcripts. The extent of splicing factor disruption, and the degree of inhibition of splicing, are proportional to the number of heptapeptides added to the protein. The above results indicate a functional interaction between Pol II's CTD and pre-mRNA splicing.

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