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Abstract
BackgroundAlternative splicing (AS) is an important mRNA maturation step that allows increased variability and diversity of proteins in eukaryotes. AS is dysregulated in numerous diseases, and its implication in the carcinogenic process is well known. However, progress in understanding how oncogenic viruses modulate splicing, and how this modulation is involved in viral oncogenicity has been limited. Epstein-Barr virus (EBV) is involved in various cancers, and its EBNA1 oncoprotein is the only viral protein expressed in all EBV malignancies.MethodsIn the present study, the ability of EBNA1 to modulate the AS of cellular genes was assessed using a high-throughput RT-PCR approach to examine AS in 1238 cancer-associated genes. RNA immunoprecipitation coupled to RNA sequencing (RIP-Seq) assays were also performed to identify cellular mRNAs bound by EBNA1.ResultsUpon EBNA1 expression, we detected modifications to the AS profiles of 89 genes involved in cancer. Moreover, we show that EBNA1 modulates the expression levels of various splicing factors such as hnRNPA1, FOX-2, and SF1. Finally, RNA immunoprecipitation coupled to RIP-Seq assays demonstrate that EBNA1 immunoprecipitates specific cellular mRNAs, but not the ones that are spliced differently in EBNA1-expressing cells.ConclusionThe EBNA1 protein can modulate the AS profiles of numerous cellular genes. Interestingly, this modulation protein does not require the RNA binding activity of EBNA1. Overall, these findings underline the novel role of EBNA1 as a cellular splicing modulator.
Highlights
Alternative splicing (AS) is an important mRNA maturation step that allows increased variability and diversity of proteins in eukaryotes
Expression of EBNA1 in HEK293T The EBNA1 protein is interesting in regards to viral carcinogenesis as it is the only Epstein-Barr virus (EBV) protein expressed in all EBV-positive cancers [21]
Our result indicated that nearly 7000 reads originated from the EBNA1 mRNA in the HEK293T-EBNA1, and no read was detectable in the control HEK293T (Additional file 1: Figure S8)
Summary
Alternative splicing (AS) is an important mRNA maturation step that allows increased variability and diversity of proteins in eukaryotes. AS, as opposed to constitutive splicing, leads to different arrangement of exons, retained introns, and splice-sites for the same pre-messenger RNA (pre-mRNA). This allows the same pre-mRNA to be processed into different isoform-coding mature mRNAs, sometimes even with opposing functions at the protein level. Sindbis virus sequestration of HuR protein in the cytoplasm through multiple HuR 3′-UTR binding sequences in viral genomic and subgenomic RNAs modifies the splicing of PCBP2 and DST transcripts (a complete list of all gene names used in this manuscript and their official complete name is included in Additional file 1: Table S1) [6]. The poliovirus protease 2A (2Apro) is able to change the cellular localization of HuR, TIA1 and TIAR, thereby impacting the splicing of the apoptotic gene FAS [7]
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