Inhibition of splicing by serine-arginine rich protein 55 (SRp55) causes the appearance of partially spliced HIV-1 mRNAs in the cytoplasm

Tranell, Anna; Tingsborg, Susanne; Fenyõ, Éva Mária; Schwartz, Stefan

doi:10.1016/j.virusres.2011.02.010

Cited by 11 publications

(13 citation statements)

References 57 publications

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“…We have shown that the SRSF6 splicing factor binds to the 5′end of the Htt gene with an expanded CAG repeat, consistent with its known recognition motif (18). SRSF6 regulates splicing and facilitates translation of partially spliced transcripts (19,20). SR proteins might also sequester U1 small nuclear ribonucleoprotein complexes (21), a phenomenon that promotes polyadenylation from cryptic polyA signals within introns (22).…”

Section: Discussionmentioning

confidence: 62%

Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease

Sathasivam

Neueder

Gipson

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

440

452

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Huntington disease (HD) is a devastating, late-onset, inherited neurodegenerative disorder that manifests with personality changes, movement disorders, and cognitive decline. It is caused by a CAG repeat expansion in exon 1 of the HTT gene that translates to a polyglutamine tract in the huntingtin protein (HTT). The formation of HTT fragments has been implicated as an essential step in the molecular pathogenesis of HD and several proteases that cleave HTT have been identified. However, the importance of smaller N-terminal fragments has been highlighted by their presence in HD postmortem brains and by the fact that nuclear inclusions are only detected by antibodies to the N terminus of HTT. Despite an intense research effort, the precise length of these fragments and the mechanism by which they are generated remains unknown. Here we show that CAG repeat lengthdependent aberrant splicing of exon 1 HTT results in a short polyadenylated mRNA that is translated into an exon 1 HTT protein. Given that mutant exon 1 HTT proteins have consistently been shown to be highly pathogenic in HD mouse models, the aberrant splicing of HTT mRNA provides a mechanistic basis for the molecular pathogenesis of HD. RNA-targeted therapeutic strategies designed to lower the levels of HTT are under development. Many of these approaches would not prevent the production of exon 1 HTT and should be reviewed in light of our findings.exon 1 huntingtin | huntingtin fragment | mis-splicing | SRSF6

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Section: Discussionmentioning

confidence: 62%

Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease

Sathasivam

Neueder

Gipson

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

440

452

View full text Add to dashboard Cite

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“…A few studies have begun to explore small molecule therapy to disrupt HIV-1 splicing (15,19). Several factors could be responsible for the differences we observed between HOS and T cells, including hnRNP A/B and H, SC35, SF2/ASF and SRp40 (53,54).…”

Section: Discussionmentioning

confidence: 99%

Dynamic regulation of HIV-1 mRNA populations analyzed by single-molecule enrichment and long-read sequencing

Ocwieja

Sherrill-Mix

Mukherjee

et al. 2012

Nucleic Acids Research

127

194

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Alternative RNA splicing greatly expands the repertoire of proteins encoded by genomes. Next-generation sequencing (NGS) is attractive for studying alternative splicing because of the efficiency and low cost per base, but short reads typical of NGS only report mRNA fragments containing one or few splice junctions. Here, we used single-molecule amplification and long-read sequencing to study the HIV-1 provirus, which is only 9700 bp in length, but encodes nine major proteins via alternative splicing. Our data showed that the clinical isolate HIV-189.6 produces at least 109 different spliced RNAs, including a previously unappreciated ∼1 kb class of messages, two of which encode new proteins. HIV-1 message populations differed between cell types, longitudinally during infection, and among T cells from different human donors. These findings open a new window on a little studied aspect of HIV-1 replication, suggest therapeutic opportunities and provide advanced tools for the study of alternative splicing.

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“…22 The human SRSF6 protein has also been linked to infection with HIV-1, reportedly regulating HIV-1 mRNA processing and possibly being involved in nuclear export of spliced mRNAs. 23,24 L3MBTL1, on the other hand, is a tumor suppressor gene that appears to suppress genes and microRNAs that re-activate during tumor growth and whose expression is associated with decreased risk of death due to breast cancer. 25 We found suggestive evidence of association for anti-CMV antibody level on chromosome 14, with our top SNP located nearest to the pseudogene LOC728667.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide genetic investigation of serological measures of common infections

et al. 2015

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Populations and individuals differ in susceptibility to infections because of a number of factors, including host genetic variation. We previously demonstrated that differences in antibody titer, which reflect infection history, are significantly heritable. Here we attempt to identify the genetic factors influencing variation in these serological phenotypes. Blood samples from 41300 Mexican Americans were quantified for IgG antibody level against 12 common infections, selected on the basis of their reported role in cardiovascular disease risk: Chlamydia pneumoniae; Helicobacter pylori; Toxoplasma gondii; cytomegalovirus; herpes simplex I virus; herpes simplex II virus; human herpesvirus 6 (HHV6); human herpesvirus 8 (HHV8); varicella zoster virus; hepatitis A virus (HAV); influenza A virus; and influenza B virus. Pathogen-specific quantitative antibody levels were analyzed, as were three measures of pathogen burden. Genome-wide linkage and joint linkage and association analyses were performed using 1 million SNPs. Significant linkage (lod scores 43.0) was obtained for HHV6 (on chromosome 7), HHV8 (on chromosome 6), and HAV (on chromosome 13). SNP rs4812712 on chromosome 20 was significantly associated with C. pneumoniae (P = 5.3 × 10 −8 ). However, no genome-wide significant loci were obtained for the other investigated antibodies. We conclude that it is possible to localize host genetic factors influencing some of these antibody traits, but that further larger-scale investigations will be required to elucidate the genetic mechanisms contributing to variation in antibody levels.

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Inhibition of splicing by serine-arginine rich protein 55 (SRp55) causes the appearance of partially spliced HIV-1 mRNAs in the cytoplasm

Cited by 11 publications

References 57 publications

Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease

Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease

Dynamic regulation of HIV-1 mRNA populations analyzed by single-molecule enrichment and long-read sequencing

Genome-wide genetic investigation of serological measures of common infections

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