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Human nuclear Dicer restricts the deleterious accumulation of endogenous double-stranded RNA.

White E, Schlackow M, Kamieniarz-Gdula K, Proudfoot NJ, Gullerova M - Nat. Struct. Mol. Biol. (2014)

Bottom Line: Dicer interacts with RNA polymerase II (Pol II) at actively transcribed gene loci.Our results suggest that Pol II-associated Dicer restricts endogenous dsRNA formation from overlapping noncoding-RNA transcription units.Failure to do so has catastrophic effects on cell function.

View Article: PubMed Central - PubMed

Affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.

ABSTRACT
Dicer is a central enzymatic player in RNA-interference pathways that acts to regulate gene expression in nearly all eukaryotes. Although the cytoplasmic function of Dicer is well documented in mammals, its nuclear function remains obscure. Here we show that Dicer is present in both the nucleus and cytoplasm, and its nuclear levels are tightly regulated. Dicer interacts with RNA polymerase II (Pol II) at actively transcribed gene loci. Loss of Dicer causes the appearance of endogenous double-stranded RNA (dsRNA), which in turn leads to induction of the interferon-response pathway and consequent cell death. Our results suggest that Pol II-associated Dicer restricts endogenous dsRNA formation from overlapping noncoding-RNA transcription units. Failure to do so has catastrophic effects on cell function.

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Model of nuclear Dicer functionUnder normal conditions, Dicer is recruited to loci of endogenous overlapping transcription through association with Pol II and dsRNA. Dicer then cleaves co-transcriptionally dsRNA into siRNA leading to Ago1 recruitment and establishment of the H3K9me2 mark. In cells lacking Dicer, endogenous dsRNA accumulates resulting in interferon induction and consequent cell death.
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Figure 8: Model of nuclear Dicer functionUnder normal conditions, Dicer is recruited to loci of endogenous overlapping transcription through association with Pol II and dsRNA. Dicer then cleaves co-transcriptionally dsRNA into siRNA leading to Ago1 recruitment and establishment of the H3K9me2 mark. In cells lacking Dicer, endogenous dsRNA accumulates resulting in interferon induction and consequent cell death.

Mentions: Finally, we showed that Dicer knockdown perturbs the normal cycle of low-level dsRNA synthesis and Dicer-dependent TGS resulting in accumulation of dsRNA throughout the cell. We predict that dsRNA initially formed in the nucleus escapes into the cytoplasm and triggers the interferon response leading to cellular apoptosis (Fig. 8 model). Numerous studies show that Dicer loss has severe consequences to the cell. Thus, mice lacking Dicer fail to develop beyond the embryonic stage. However, while ES cells derived from these knockout mice are viable (albeit growth impaired), ES cells lack the interferon response pathway, so explaining their viability. In contrast, this study shows that for cultured mammalian somatic cells, loss of Dicer leads to dsRNA accumulation and consequent apoptosis. We therefore predict that a major role of nuclear Dicer is to set up the right balance between heterochromatin and euchromatin. Failure of this process through Dicer knockout results in dsRNA accumulation. This results in a “last ditch” process of cellular apoptosis to eliminate misregulated cells that would otherwise lead to cell pathologies such as cancer.


Human nuclear Dicer restricts the deleterious accumulation of endogenous double-stranded RNA.

White E, Schlackow M, Kamieniarz-Gdula K, Proudfoot NJ, Gullerova M - Nat. Struct. Mol. Biol. (2014)

Model of nuclear Dicer functionUnder normal conditions, Dicer is recruited to loci of endogenous overlapping transcription through association with Pol II and dsRNA. Dicer then cleaves co-transcriptionally dsRNA into siRNA leading to Ago1 recruitment and establishment of the H3K9me2 mark. In cells lacking Dicer, endogenous dsRNA accumulates resulting in interferon induction and consequent cell death.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4129937&req=5

Figure 8: Model of nuclear Dicer functionUnder normal conditions, Dicer is recruited to loci of endogenous overlapping transcription through association with Pol II and dsRNA. Dicer then cleaves co-transcriptionally dsRNA into siRNA leading to Ago1 recruitment and establishment of the H3K9me2 mark. In cells lacking Dicer, endogenous dsRNA accumulates resulting in interferon induction and consequent cell death.
Mentions: Finally, we showed that Dicer knockdown perturbs the normal cycle of low-level dsRNA synthesis and Dicer-dependent TGS resulting in accumulation of dsRNA throughout the cell. We predict that dsRNA initially formed in the nucleus escapes into the cytoplasm and triggers the interferon response leading to cellular apoptosis (Fig. 8 model). Numerous studies show that Dicer loss has severe consequences to the cell. Thus, mice lacking Dicer fail to develop beyond the embryonic stage. However, while ES cells derived from these knockout mice are viable (albeit growth impaired), ES cells lack the interferon response pathway, so explaining their viability. In contrast, this study shows that for cultured mammalian somatic cells, loss of Dicer leads to dsRNA accumulation and consequent apoptosis. We therefore predict that a major role of nuclear Dicer is to set up the right balance between heterochromatin and euchromatin. Failure of this process through Dicer knockout results in dsRNA accumulation. This results in a “last ditch” process of cellular apoptosis to eliminate misregulated cells that would otherwise lead to cell pathologies such as cancer.

Bottom Line: Dicer interacts with RNA polymerase II (Pol II) at actively transcribed gene loci.Our results suggest that Pol II-associated Dicer restricts endogenous dsRNA formation from overlapping noncoding-RNA transcription units.Failure to do so has catastrophic effects on cell function.

View Article: PubMed Central - PubMed

Affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.

ABSTRACT
Dicer is a central enzymatic player in RNA-interference pathways that acts to regulate gene expression in nearly all eukaryotes. Although the cytoplasmic function of Dicer is well documented in mammals, its nuclear function remains obscure. Here we show that Dicer is present in both the nucleus and cytoplasm, and its nuclear levels are tightly regulated. Dicer interacts with RNA polymerase II (Pol II) at actively transcribed gene loci. Loss of Dicer causes the appearance of endogenous double-stranded RNA (dsRNA), which in turn leads to induction of the interferon-response pathway and consequent cell death. Our results suggest that Pol II-associated Dicer restricts endogenous dsRNA formation from overlapping noncoding-RNA transcription units. Failure to do so has catastrophic effects on cell function.

Show MeSH
Related in: MedlinePlus