Conservation of Virally Encoded MicroRNAs in Kaposi Sarcoma–Associated Herpesvirus in Primary Effusion Lymphoma Cell Lines and in Patients with Kaposi Sarcoma or Multicentric Castleman Disease

Marshall, Vickie; Parks, Thomas; Bagni, Rachel; Wang, Cheng Dian; Samols, Mark A.; Hu, Jianhong; Wyvil, Kathleen M.; Aleman, Karen; Little, Richard F.; Yarchoan, Robert; Renne, Rolf; Whitby, Denise

doi:10.1086/511434

Cited by 92 publications

(119 citation statements)

References 40 publications

Supporting

Mentioning

110

Contrasting

Unclassified

Order By: Relevance

“…KSHV miR-K11 has been previously shown to target many of the same mRNAs as miR-155 (Gottwein et al 2007;Skalsky et al 2007) and miR-K11 has even been shown to rescue B-cell development in miR-155-deficient mice (Boss et al 2011;Sin et al 2013). Nevertheless, it has seemed possible that miR-K11, which is highly conserved during KSHV evolution (Marshall et al 2007), might also selectively target specific host mRNAs to give an additional selective advantage to this virus, when compared with simply activating the expression of endogenous miR-155, the strategy followed by the related human γ-herpesvirus Epstein-Barr virus (Linnstaedt et al 2010). Using the PAR-CLIP technology (Hafner et al 2010), we were indeed able to identify mRNA target sites for RISCs programmed by a miR-K11 RNA duplex that were not detected in NoDice(4-25) cells transfected with a miR-155 duplex, and vice versa.…”

Section: Discussionmentioning

confidence: 99%

Derivation and characterization of Dicer- and microRNA-deficient human cells

Bogerd

Whisnant

Kennedy

et al. 2014

RNA

147

View full text Add to dashboard Cite

We have used genome editing to generate inactivating deletion mutations in all three copies of the dicer (hdcr) gene present in the human cell line 293T. As previously shown in murine ES cells lacking Dicer function, hDcr-deficient 293T cells are severely impaired for the production of mature microRNAs (miRNAs). Nevertheless, RNA-induced silencing complexes (RISCs) present in these hDcr-deficient cells are readily programmed by transfected, synthetic miRNA duplexes to repress mRNAs bearing either fully or partially complementary targets, including targets bearing incomplete seed homology to the introduced miRNA. Using these hDcr-deficient 293T cells, we demonstrate that human pre-miRNA processing can be effectively rescued by ectopic expression of the Drosophila Dicer 1 protein, but only in the presence of the PB isoform of Loquacious (Loqs-PB), the fly homolog of the hDcr cofactor TRBP. In contrast, Drosophila Dicer 2, even in the presence of its cofactors Loqs-PD and R2D2, was unable to support human pre-miRNA processing. Interestingly, although ectopic Drosophila Dicer 1/Loqs-PB or hDcr both rescued pre-miRNA processing effectively in these hDcr-deficient cells, there were significant differences in the ratio of the miRNA isoforms that were produced, especially in the case of miR-30 family members, and we also noted differences in the relative expression level of miRNAs vs. passenger strands for a subset of human miRNAs. These data demonstrate that the mechanisms underlying the accurate processing of pre-miRNAs are largely, but not entirely, conserved between mammalian and insect cells.

show abstract

Section: Discussionmentioning

confidence: 99%

Derivation and characterization of Dicer- and microRNA-deficient human cells

Bogerd

Whisnant

Kennedy

et al. 2014

RNA

147

View full text Add to dashboard Cite

show abstract

“…This promoter also governs the expression of 12 pre-miRNAs (Figure 4), which can be processed to yield a total of 18 mature miRNAs (98)(99)(100)(101)(102). All of these latent products have been found to be expressed in KS spindle cells as well as PEL cells (103)(104)(105). A second locus, expressed in latent PEL cells, encodes the v-IRF3 (or LANA-2) protein, a member of the IRF superfamily that dominantly inhibits IFN induction (106).…”

Section: How Does Kshv Infection Predispose To Ks?mentioning

confidence: 99%

KSHV and the pathogenesis of Kaposi sarcoma: listening to human biology and medicine

Ganem¹

2010

J. Clin. Invest.

331

380

View full text Add to dashboard Cite

“…Like all herpesviruses, KSHV has a large, double-stranded DNA genome (z160 kb) (Russo et al 1996). KSHV encodes more than 85 protein-coding genes, and at least 12 pre-miRNAs that give rise to at least 17 different miRNAs (16 different 5p or 3p miRNAs, and a single-nucleotide-edited miRNA) that are highly conserved (Marshall et al 2007). The pre-miRNAs are clustered in a single z4-kb region of the genome and are encoded in a polycistronic fashion from any of several different transcripts made during latent infection (Pearce et al 2005;.…”

Section: Introductionmentioning

confidence: 99%

Small RNA profiling reveals antisense transcription throughout the KSHV genome and novel small RNAs

Lin¹,

Kincaid²,

Arasappan³

et al. 2010

RNA

View full text Add to dashboard Cite

Kaposi's sarcoma-associated herpesvirus (KSHV) is a human tumor virus that encodes 12 precursor microRNAs (pre-miRNAs) that give rise to 17 different known~22-nucleotide (nt) effector miRNAs. Like all herpesviruses, KSHV has two modes of infection: (1) a latent mode whereby only a subset of viral genes are expressed and (2) a lytic mode during which the full remaining viral genes are expressed. To date, KSHV miRNAs have been mostly identified via analysis of cells that are undergoing latent infection. Here, we developed a method to profile small RNAs (~18-75 nt) from populations of cells undergoing predominantly lytic infection. Using two different next-generation sequencing platforms, we cloned and sequenced both premiRNAs and derivative miRNAs. Our analysis shows that the vast majority of viral and host 5p miRNAs are co-terminal with the 59 end of the cloned pre-miRNAs, consistent with both being defined by microprocessor cleavage. We report the complete repertoire (25 total) of 5p and 3p derivative miRNAs from all 12 previously described KSHV pre-miRNAs. Two KSHV premiRNAs, pre-miR-K12-8 and pre-miR-K12-12, encode abundant derivative miRNAs from the previously unreported strands of the pre-miRNA. We identify several novel small RNAs of low abundance, including viral miRNA-offset-RNAs (moRNAs), and antisense viral miRNAs (miRNA-AS) that are encoded antisense to previously reported KSHV pre-miRNAs. Finally, we observe widespread antisense transcription relative to known coding sequences during lytic replication. Despite the enormous potential to form double-stranded RNA in KSHV-infected cells, we observe no evidence for the existence of abundant viral-derived small interfering RNAs (siRNAs).

show abstract

Conservation of Virally Encoded MicroRNAs in Kaposi Sarcoma–Associated Herpesvirus in Primary Effusion Lymphoma Cell Lines and in Patients with Kaposi Sarcoma or Multicentric Castleman Disease

Abstract: These data demonstrate that KSHV microRNA genes are under tight selection in vivo and suggest that they contribute to the biological activity and possibly the pathogenesis of KSHV-associated malignancies.

Cited by 92 publications

References 40 publications

Derivation and characterization of Dicer- and microRNA-deficient human cells

Derivation and characterization of Dicer- and microRNA-deficient human cells

KSHV and the pathogenesis of Kaposi sarcoma: listening to human biology and medicine

Small RNA profiling reveals antisense transcription throughout the KSHV genome and novel small RNAs

Contact Info

Product

Resources

About