Characterization of the Influence of Mediator Complex in HIV-1 Transcription

Ruiz, Alba; Pauls, Eduardo; Badía, Roger; Riveira-Muñoz, Eva; Clotet, Bonaventura; Ballana, Ester; Esté, José A.

doi:10.1074/jbc.m114.570341

Cited by 30 publications

(23 citation statements)

References 43 publications

(53 reference statements)

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“…Examples include ACIN1 which is identified as a HIV-1 Tat interacting protein52, CHMP4B which is critical for HIV-1 membrane budding via ESCRT pathway53, NMT1 which is involved in targeting and assembly of HIV-1 Gag proteins to plasma membrane via N-myristoylation54, MAPK1 which interacts with 10 HIV-1 proteins and may play multiple roles in HIV-1 replication55. NFAT5 which interacts with an enhancer binding site in LTR of HIV-1 to enable replication in human primary macrophages56, MED1, a subunit of mediator complex which plays a critical role in HIV-1 transcription and infectivity5758 and RBM14 which encodes a nucleic acid binding protein that associates with XPO1 to export incompletely spliced HIV-1 transcripts59. Although combined effects of RNA editing of hundreds of genes on HIV-1 replication is unknown, A3G may alter the host environment by means of RNA editing to antagonize HIV-1 infection.…”

Section: Discussionmentioning

confidence: 99%

The double-domain cytidine deaminase APOBEC3G is a cellular site-specific RNA editing enzyme

Sharma

Patnaik

Taggart

et al. 2016

Sci Rep

113

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APOBEC3G is a cytidine deaminase with two homologous domains and restricts retroelements and HIV-1. APOBEC3G deaminates single-stranded DNAs via its C-terminal domain, whereas the N-terminal domain is considered non-catalytic. Although APOBEC3G is known to bind RNAs, APOBEC3G-mediated RNA editing has not been observed. We recently discovered RNA editing by the single-domain enzyme APOBEC3A in innate immune cells. To determine if APOBEC3G is capable of RNA editing, we transiently expressed APOBEC3G in the HEK293T cell line and performed transcriptome-wide RNA sequencing. We show that APOBEC3G causes site-specific C-to-U editing of mRNAs from over 600 genes. The edited cytidines are often flanked by inverted repeats, but are largely distinct from those deaminated by APOBEC3A. We verified protein-recoding RNA editing of selected genes including several that are known to be involved in HIV-1 infectivity. APOBEC3G co-purifies with highly edited mRNA substrates. We find that conserved catalytic residues in both cytidine deaminase domains are required for RNA editing. Our findings demonstrate the novel RNA editing function of APOBEC3G and suggest a role for the N-terminal domain in RNA editing.

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Section: Discussionmentioning

confidence: 99%

The double-domain cytidine deaminase APOBEC3G is a cellular site-specific RNA editing enzyme

Sharma

Patnaik

Taggart

et al. 2016

Sci Rep

113

View full text Add to dashboard Cite

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“…37, 38 Transfected monocytes were left untreated overnight and then differentiated to macrophages as described above. Cell viability was quantified by flow cytometry in a forward-versus side-scatter (FCS and SSC, respectively) plot as described by Blanco et al Viruses and virus infections R5-tropic HIV-1 strain BaL was grown in stimulated PBMC and titrated for its use in MDM.…”

Section: Compoundsmentioning

confidence: 99%

Cyclin D3-dependent control of the dNTP pool and HIV-1 replication in human macrophages

et al. 2015

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Cyclins control the activation of cyclin-dependent kinases (CDK), which in turn, control the cell cycle and cell division. Intracellular availability of deoxynucleotides (dNTP) plays a fundamental role in cell cycle progression. SAM domain and HD domain-containing protein 1 (SAMHD1) degrades nucleotide triphosphates and controls the size of the dNTP pool. SAMHD1 activity appears to be controlled by CDK. Here, we show that knockdown of cyclin D3 a partner of CDK6 and E2 a partner of CDK2 had a major impact in SAMHD1 phosphorylation and inactivation and led to decreased dNTP levels and inhibition of HIV-1 at the reverse transcription step in primary human macrophages. The effect of cyclin D3 RNA interference was lost after degradation of SAMHD1 by HIV-2 Vpx, demonstrating the specificity of the mechanism. Cyclin D3 inhibition correlated with decreased activation of CDK2. Our results confirm the fundamental role of the CDK6-cyclin D3 pair in controlling CDK2-dependent SAMHD1 phosphorylation and dNTP pool in primary macrophages.

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“…Consistent with its role in Ty1 retromobility, Mediator also plays an important part of the host cell response to retroviruses such as HIV-1 [13,14,76]. Human Med4, and Med7 (orthologs to yeast Med4, and Med7, respectively), and Med28 (no known yeast orthologs) were identified as HIV-1 dependency factors [13,14].…”

Section: Discussionmentioning

confidence: 99%

“…Human Med4, and Med7 (orthologs to yeast Med4, and Med7, respectively), and Med28 (no known yeast orthologs) were identified as HIV-1 dependency factors [13,14]. Additionally, Med6, Med8, Med11, Med17, Med19, Med20, Med26, Med27, and Med31 (all of which have yeast orthologs of the same name with the exception of Med19, Med26, and Med27) were shown to be important activators of HIV-1 transcription [14,76]. While the evidence of Mediator’s role in Ty1 TSS selection contrasts mechanistically with the role that Mediator takes in regulating HIV-1 transcription, the results presented here provide a novel mechanism by which Mediator can influence retroviral transcripts [76].…”

Section: Discussionmentioning

confidence: 99%

The Mediator co-activator complex regulates Ty1 retromobility by controlling the balance between Ty1i and Ty1 promoters

Salinero

Knoll

Zhu

et al. 2017

Preprint

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4The Ty1 retrotransposons present in the genome of Saccharomyces cerevisiae belong to the large class 3 5 of mobile genetic elements that replicate via an RNA intermediary and constitute a significant portion of 3 6 most eukaryotic genomes. The retromobility of Ty1 is regulated by numerous host factors, including 3 7 several subunits of the Mediator transcriptional co-activator complex. In spite of its known function in 3 8 the nucleus, previous studies have implicated Mediator in the regulation of post-translational steps in 3 9 Ty1 retromobility. To resolve this paradox, we systematically examined the effects of deleting non-4 0 essential Mediator subunits on the frequency of Ty1 retromobility and levels of retromobility 4 1 intermediates. Our findings reveal that loss of distinct Mediator subunits alters Ty1 retromobility 4 2 positively or negatively over a >10,000-fold range by regulating the ratio of an internal transcript, Ty1i, 4 3 to the genomic Ty1 transcript. Ty1i RNA encodes a dominant negative inhibitor of Ty1 retromobility 4 4 that blocks virus-like particle maturation and cDNA synthesis. These results resolve the conundrum of 4 5

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Characterization of the Influence of Mediator Complex in HIV-1 Transcription

Cited by 30 publications

References 43 publications

The double-domain cytidine deaminase APOBEC3G is a cellular site-specific RNA editing enzyme

The double-domain cytidine deaminase APOBEC3G is a cellular site-specific RNA editing enzyme

Cyclin D3-dependent control of the dNTP pool and HIV-1 replication in human macrophages

The Mediator co-activator complex regulates Ty1 retromobility by controlling the balance between Ty1i and Ty1 promoters

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