Retroviral RNA Processing.

This review is an accompaniment to a Special Issue on "Retroviral RNA Processing". It discusses post-transcriptional regulation of retroviruses, ranging from the ancient foamy viruses to more modern viruses, such as HIV-1, HTLV-1, Rous sarcoma virus, murine leukemia virus, mouse mammary tumor virus, and Mason-Pfizer monkey virus. This review is not comprehensive.

mC Goes Viral.

In this issue of Cell Host & Microbe, Courtney et al. (2019a) find that HIV-1 genomic RNA has much more mC than cellular mRNA. Deleting the m5C "writer" NSUN2 decreases HIV-1 mC levels, promotes translation of the HIV-1 5' gag gene, and alters splicing at the A2 site.

A Novel Long Non-Coding RNA in the hTERT Promoter Region Regulates hTERT Expression.

A novel antisense transcript was identified in the human telomerase reverse transcriptase () promoter region, suggesting that the promoter is bidirectional. This transcript, named antisense promoter-associated () RNA, is a 1.6 kb long non-coding RNA.

ALV Integration-Associated Hypomethylation at the TERT Promoter Locus.

Avian leukosis virus (ALV) is a simple retrovirus that can induce B-cell lymphoma in chicken(s) and other birds by insertional mutagenesis. The promoter region of telomerase reverse transcriptase (TERT) has been identified as an important integration site for tumorigenesis. Tumors with TERT promoter integrations are associated with increased TERT expression.

Selection for avian leukosis virus integration sites determines the clonal progression of B-cell lymphomas.

Avian leukosis virus (ALV) is a simple retrovirus that causes a wide range of tumors in chickens, the most common of which are B-cell lymphomas. The viral genome integrates into the host genome and uses its strong promoter and enhancer sequences to alter the expression of nearby genes, frequently inducing tumors. In this study, we compare the preferences for ALV integration sites in cultured cells and in tumors, by analysis of over 87,000 unique integration sites.

Integration of ALV into and genes in B-cell lymphomas promotes cell immortalization, migration and survival.

Avian leukosis virus induces tumors in chickens by integrating into the genome and altering expression of nearby genes. Thus, ALV can be used as an insertional mutagenesis tool to identify novel genes involved in tumorigenesis. Deep sequencing analysis of viral integration sites has identified and as common integration sites in ALV-induced B-cell lymphomas, suggesting a potential role in driving oncogenesis.

Rous Sarcoma Virus RNA Stability Element Inhibits Deadenylation of mRNAs with Long 3'UTRs.

All retroviruses use their full-length primary transcript as the major mRNA for Group-specific antigen (Gag) capsid proteins. This results in a long 3' untranslated region (UTR) downstream of the termination codon. In the case of Rous sarcoma virus (RSV), there is a 7 kb 3'UTR downstream of the terminator, containing the , , and genes.

The FACT Complex Promotes Avian Leukosis Virus DNA Integration.

All retroviruses need to integrate a DNA copy of their genome into the host chromatin. Cellular proteins regulating and targeting lentiviral and gammaretroviral integration in infected cells have been discovered, but the factors that mediate alpharetroviral avian leukosis virus (ALV) integration are unknown. In this study, we have identified the FACT protein complex, which consists of SSRP1 and Spt16, as a principal cellular binding partner of ALV integrase (IN).

Lack of TERT Promoter Mutations in Human B-Cell Non-Hodgkin Lymphoma.

Non-Hodgkin lymphomas (NHL) are a heterogeneous group of immune cell neoplasms that comprise molecularly distinct lymphoma subtypes. Recent work has identified high frequency promoter point mutations in the telomerase reverse transcriptase () gene of different cancer types, including melanoma, glioma, liver and bladder cancer. promoter mutations appear to correlate with increased TERT expression and telomerase activity in these cancers.

Avian Leukosis Virus Activation of an Antisense RNA Upstream of TERT in B-Cell Lymphomas.

Unlabelled: Avian leukosis virus (ALV) induces tumors by integrating its proviral DNA into the chicken genome and altering the expression of nearby genes via strong promoter and enhancer elements. Viral integration sites that contribute to oncogenesis are selected in tumor cells. Deep-sequencing analysis of B-cell lymphoma DNA confirmed that the telomerase reverse transcriptase (TERT) gene promoter is a common ALV integration target.

Polypyrimidine tract binding protein 1 protects mRNAs from recognition by the nonsense-mediated mRNA decay pathway.

The nonsense-mediated mRNA decay (NMD) pathway degrades mRNAs containing long 3'UTRs to perform dual roles in mRNA quality control and gene expression regulation. However, expansion of vertebrate 3'UTR functions has required a physical expansion of 3'UTR lengths, complicating the process of detecting nonsense mutations. We show that the polypyrimidine tract binding protein 1 (PTBP1) shields specific retroviral and cellular transcripts from NMD.

Common Viral Integration Sites Identified in Avian Leukosis Virus-Induced B-Cell Lymphomas.

Unlabelled: Avian leukosis virus (ALV) induces B-cell lymphoma and other neoplasms in chickens by integrating within or near cancer genes and perturbing their expression. Four genes--MYC, MYB, Mir-155, and TERT--have previously been identified as common integration sites in these virus-induced lymphomas and are thought to play a causal role in tumorigenesis. In this study, we employ high-throughput sequencing to identify additional genes driving tumorigenesis in ALV-induced B-cell lymphomas.

Complete genome sequence of an american avian leukosis virus subgroup j isolate that causes hemangiomas and myeloid leukosis.

We report the complete genome sequence of avian leukosis virus subgroup J (ALV-J) isolate PDRC-59831, which causes myeloid leukosis and hemangiomas in chickens. This is an American ALV-J isolate, which was found in a 38-week-old broiler breeder chicken on a farm in Georgia in 2007.

The MET gene is a common integration target in avian leukosis virus subgroup J-induced chicken hemangiomas.

Unlabelled: Avian leukosis virus subgroup J (ALV-J) is a simple retrovirus that can cause hemangiomas and myeloid tumors in chickens and is currently a major economic problem in Asia. Here we characterize ALV-J strain PDRC-59831, a newly studied U.S.

Retroviral strategy to stabilize viral RNA.

Unspliced Rous sarcoma virus (RSV) retroviral mRNA undergoes nonsense-mediated RNA decay (NMD) if it has premature termination codons in the gag gene. However, its normal gag termination codon is not subject to NMD despite being 7kb from the 3' poly(A) sequence. An RNA stability element (RSE) has been identified immediately downstream of gag in the RSV genome.

Avian retroviral replication.

Avian retroviruses were originally identified as cancer-inducting filterable agents in chicken neoplasms at the beginning of the 20th century. Since their discovery, the study of these simple retroviruses has contributed greatly to our understanding of viral replication and cancer. Avian retroviruses continue to evolve and have great economic importance in the poultry industry worldwide.

Posttranscriptional regulation of retroviral gene expression: primary RNA transcripts play three roles as pre-mRNA, mRNA, and genomic RNA.

After reverse transcription of the retroviral RNA genome and integration of the DNA provirus into the host genome, host machinery is used for viral gene expression along with viral proteins and RNA regulatory elements. Here, we discuss co-transcriptional and posttranscriptional regulation of retroviral gene expression, comparing simple and complex retroviruses. Cellular RNA polymerase II synthesizes full-length viral primary RNA transcripts that are capped and polyadenylated.

Exclusion of exon 2 is a common mRNA splice variant of primate telomerase reverse transcriptases.

Telomeric sequences are added by an enzyme called telomerase that is made of two components: a catalytic protein called telomerase reverse transcriptase (TERT) and an integral RNA template (TR). Telomerase expression is tightly regulated at each step of gene expression, including alternative splicing of TERT mRNA. While over a dozen different alternative splicing events have been reported for human TERT mRNA, these were all in the 3' half of the coding region.

Unexpected diversity and expression of avian endogenous retroviruses.

Endogenous retroviruses (ERVs) were identified and characterized in three avian genomes to gain insight into early retroviral evolution. Using the computer program RetroTector to detect relatively intact ERVs, we identified 500 ERVs in the chicken genome, 150 in the turkey genome, and 1,200 in the zebra finch genome. Previous studies suggested that endogenous alpharetroviruses were present in chicken genomes.

Splicing of internal large exons is defined by novel cis-acting sequence elements.

Human internal exons have an average size of 147 nt, and most are <300 nt. This small size is thought to facilitate exon definition. A small number of large internal exons have been identified and shown to be alternatively spliced.

The structure and function of the rous sarcoma virus RNA stability element.

For simple retroviruses, such as the Rous sarcoma virus (RSV), post-transcriptional control elements regulate viral RNA splicing, export, stability, and packaging into virions. These RNA sequences interact with cellular host proteins to regulate and facilitate productive viral infections. One such element, known as the RSV stability element (RSE), is required for maintaining stability of the full-length unspliced RNA.

Structural features in the Rous sarcoma virus RNA stability element are necessary for sensing the correct termination codon.

Background: Nonsense-mediated mRNA decay (NMD) is an mRNA quality control mechanism that selectively recognizes and targets for degradation mRNAs containing premature termination codons. Retroviral full-length RNA is presented to the host translation machinery with characteristics rarely observed among host cell mRNAs: a long 3' UTR, retained introns, and multiple open reading frames. As a result, the viral RNA is predicted to be recognized by the host NMD machinery and degraded.

Reticuloendotheliosis virus strain T induces miR-155, which targets JARID2 and promotes cell survival.

The oncogenic microRNA miR-155 is upregulated by several oncogenic viruses. The precursor of miR-155, termed bic, was first observed to cooperate with myc in chicken B-cell lymphomas induced by avian leukosis proviral integrations. We identified another oncogenic retrovirus, reticuloendotheliosis virus strain T (REV-T), that upregulates miR-155 in chicken embryo fibroblasts.