Oncogenes and RNA splicing of human tumor viruses

Ajiro, Masahiko; Zheng, Zhi-Ming

doi:10.1038/emi.2014.62

Cited by 49 publications

(68 citation statements)

References 245 publications

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“…Two major polycistronic pre-mRNAs, early and late pre-mRNAs, are transcribed from the high-risk HPV genome. Alternative RNA splicing of the HPV polycistronic pre-mRNAs plays a crucial role in regulation of viral gene expression (2,3). Although the molecular mechanisms that regulate alternative RNA splicing of bovine papillomavirus type 1 (BPV-1) (4-11) and HPV16 pre-mRNA transcripts (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22) have been extensively studied in the past, a full transcription map of HPV18 in productive infection, the second most prevalent high-risk HPV genotype in association with cervical cancer (23), was constructed only recently (24), and the mechanistic regulation of HPV18 RNA splicing remains poorly investigated.…”

mentioning

confidence: 99%

Serine/Arginine-Rich Splicing Factor 3 and Heterogeneous Nuclear Ribonucleoprotein A1 Regulate Alternative RNA Splicing and Gene Expression of Human Papillomavirus 18 through Two Functionally Distinguishable cis Elements

Ajiro

Tang

Doorbar

et al. 2016

J Virol

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Human papillomavirus 18 (HPV18) is the second most common oncogenic HPV type associated with cervical, anogenital, and oropharyngeal cancers. Like other oncogenic HPVs, HPV18 encodes two major (one early and one late) polycistronic premRNAs that are regulated by alternative RNA splicing to produce a repertoire of viral transcripts for the expression of individual viral genes. However, RNA cis-regulatory elements and trans-acting factors contributing to HPV18 alternative RNA splicing remain unknown. In this study, an exonic splicing enhancer (ESE) in the nucleotide (nt) 3520 to 3550 region in the HPV18 genome was identified and characterized for promotion of HPV18 929^3434 splicing and E1^E4 production through interaction with SRSF3, a host oncogenic splicing factor differentially expressed in epithelial cells and keratinocytes. Introduction of point mutations in the SRSF3-binding site or knockdown of SRSF3 expression in cells reduces 929^3434 splicing and E1^E4 production but activates other, minor 929^3465 and 929^3506 splicing. Knockdown of SRSF3 expression also enhances the expression of E2 and L1 mRNAs. An exonic splicing silencer (ESS) in the HPV18 nt 612 to 639 region was identified as being inhibitory to the 233^416 splicing of HPV18 E6E7 pre-mRNAs via binding to hnRNP A1, a well-characterized, abundantly and ubiquitously expressed RNA-binding protein. Introduction of point mutations into the hnRNP A1-binding site or knockdown of hnRNP A1 expression promoted 233^416 splicing and reduced E6 expression. These data provide the first evidence that the alternative RNA splicing of HPV18 pre-mRNAs is subject to regulation by viral RNA cis elements and host trans-acting splicing factors. IMPORTANCEExpression of HPV18 genes is regulated by alternative RNA splicing of viral polycistronic pre-mRNAs to produce a repertoire of viral early and late transcripts. RNA cis elements and trans-acting factors contributing to HPV18 alternative RNA splicing have been discovered in this study for the first time. The identified ESS at the E7 open reading frame (ORF) prevents HPV18 233^416 splicing in the E6 ORF through interaction with a host splicing factor, hnRNP A1, and regulates E6 and E7 expression of the early E6E7 polycistronic pre-mRNA. The identified ESE at the E1^E4 ORF promotes HPV18 929^3434 splicing of both viral early and late pre-mRNAs and E1^E4 production through interaction with SRSF3. This study provides important observations on how alternative RNA splicing of HPV18 pre-mRNAs is subject to regulation by viral RNA cis elements and host splicing factors and offers potential therapeutic targets to overcome HPV-related cancer.H igh-risk human papillomavirus (HPV) is associated with more than 95% of cervical cancer, 40 to 90% of anogenital cancer, and 10 to 60% of oropharyngeal cancer with geographic variation (1). Two major polycistronic pre-mRNAs, early and late pre-mRNAs, are transcribed from the high-risk HPV genome. Alternative RNA splicing of the HPV polycistronic pre-mRNAs plays a crucial role in regu...

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confidence: 99%

Serine/Arginine-Rich Splicing Factor 3 and Heterogeneous Nuclear Ribonucleoprotein A1 Regulate Alternative RNA Splicing and Gene Expression of Human Papillomavirus 18 through Two Functionally Distinguishable cis Elements

Ajiro

Tang

Doorbar

et al. 2016

J Virol

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“…LMP1 is transcribed from two different promoters producing two LMP1 isoforms, with one isoform being a shorter version lacking the N terminus. This shorter version is non-coding and acts as a negative regulator of the larger oncogenic isoform 104. Other oncogenes expressed by EBV include the EBV nuclear antigens (EBNAs).…”

Section: Oncogenic Viruses Angiogenesis and Aids-related Cancersmentioning

confidence: 99%

“…The levels of Merkel cell polyomavirus infection is higher in HIV-infected individuals 105. Alternative splicing of the early pre-mRNAs of the virus produce four isoforms (LT, sT1, sT2, and 57kT) 104. The T antigens have different functions, with the large T- and small t-antigen exerting their oncogenic effects by inhibiting tumor suppressors, activating tumor promoters, preventing apoptosis, inducing angiogenesis, stimulating metastasis, translation, and inhibiting E3 ubiquitin ligase activity 106…”

Section: Oncogenic Viruses Angiogenesis and Aids-related Cancersmentioning

confidence: 99%

Abnormalities in alternative splicing of angiogenesis-related genes and their role in HIV-related cancers

Mthembu¹,

Mbita²,

Hull³

et al. 2017

HIV

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Alternative splicing of mRNA leads to an increase in proteome biodiversity by allowing the generation of multiple mRNAs, coding for multiple protein isoforms of various structural and functional properties from a single primary pre-mRNA transcript. The protein isoforms produced are tightly regulated in normal development but are mostly deregulated in various cancers. In HIV-infected individuals with AIDS, there is an increase in aberrant alternative splicing, resulting in an increase in HIV/AIDS-related cancers, such as Kaposi’s sarcoma, non-Hodgkin’s lymphoma, and cervical cancer. This aberrant splicing leads to abnormal production of protein and is caused by mutations in cis-acting elements or trans-acting factors in angiogenesis-related genes. Restoring the normal regulation of alternative splicing of angiogenic genes would alter the expression of protein isoforms and may confer normal cell physiology in patients with these cancers. This review highlights the abnormalities in alternative splicing of angiogenesis-related genes and their implication in HIV/AIDS-related cancers. This allows us to gain an insight into the pathogenesis of HIV/AIDS-related cancer and in turn elucidate the therapeutic potential of alternatively spliced genes in HIV/AIDS-related malignancies.

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“…Different mechanisms by which HCV, HBV and HDV contribute to the development and progression of HCC have been proposed. These include continuous antiviral inflammatory responses, ongoing immune clearance of infected cells and hepatocyte regeneration which all occur during chronic infection and lead to genetic and epigenetic changes that put patients at increased risk for HCC establishment [6,7]. …”

Section: Introductionmentioning

confidence: 99%

Hepatocarcinogenesis associated with hepatitis B, delta and C viruses

Shirvani-Dastgerdi

Schwartz

Ploß

2016

Current Opinion in Virology

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Globally, over half a billion people are persistently infected with hepatitis B (HBV) and/or hepatitis C viruses. Chronic HBV and HCV infection frequently lead to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Co-infections with hepatitis delta virus (HDV), a subviral satellite requiring HBV for its propagation, accelerates the progression of liver disease toward HCC. The mechanisms by which these viruses cause malignant transformation, culminating in HCC, remain incompletely understood, partially due to the lack of adequate experimental models for dissecting these complex disease processes in vivo.

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Oncogenes and RNA splicing of human tumor viruses

Cited by 49 publications

References 245 publications

Serine/Arginine-Rich Splicing Factor 3 and Heterogeneous Nuclear Ribonucleoprotein A1 Regulate Alternative RNA Splicing and Gene Expression of Human Papillomavirus 18 through Two Functionally Distinguishable cis Elements

Serine/Arginine-Rich Splicing Factor 3 and Heterogeneous Nuclear Ribonucleoprotein A1 Regulate Alternative RNA Splicing and Gene Expression of Human Papillomavirus 18 through Two Functionally Distinguishable cis Elements

Abnormalities in alternative splicing of angiogenesis-related genes and their role in HIV-related cancers

Hepatocarcinogenesis associated with hepatitis B, delta and C viruses

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