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MOV10 RNA helicase is a potent inhibitor of retrotransposition in cells.

Goodier JL, Cheung LE, Kazazian HH - PLoS Genet. (2012)

Bottom Line: However, unlike MOV10, these other helicases do not strongly inhibit retrotransposition, an activity dependent upon intact helicase domains.Therefore, the host has evolved defense mechanisms to protect against retrotransposition, an arsenal we are only beginning to understand.With homologs in other vertebrates, insects, and plants, MOV10 may represent an ancient and innate form of immunity against both infective viruses and endogenous retroelements.

View Article: PubMed Central - PubMed

Affiliation: McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. jgoodier@jhmi.edu

ABSTRACT
MOV10 protein, a putative RNA helicase and component of the RNA-induced silencing complex (RISC), inhibits retrovirus replication. We show that MOV10 also severely restricts human LINE1 (L1), Alu, and SVA retrotransposons. MOV10 associates with the L1 ribonucleoprotein particle, along with other RNA helicases including DDX5, DHX9, DDX17, DDX21, and DDX39A. However, unlike MOV10, these other helicases do not strongly inhibit retrotransposition, an activity dependent upon intact helicase domains. MOV10 association with retrotransposons is further supported by its colocalization with L1 ORF1 protein in stress granules, by cytoplasmic structures associated with RNA silencing, and by the ability of MOV10 to reduce endogenous and ectopic L1 expression. The majority of the human genome is repetitive DNA, most of which is the detritus of millions of years of accumulated retrotransposition. Retrotransposons remain active mutagens, and their insertion can disrupt gene function. Therefore, the host has evolved defense mechanisms to protect against retrotransposition, an arsenal we are only beginning to understand. With homologs in other vertebrates, insects, and plants, MOV10 may represent an ancient and innate form of immunity against both infective viruses and endogenous retroelements.

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Polycomb group (PcG) multiprotein PRC1-like complex component Chromobox homolog 7 (CBX7) associates with the L1-RNP and inhibits retrotransposition.(A) Lanes 1–3: CBX7 binds weakly with the L1 RNP in an RNA-dependent manner. Lanes 4–9: Co-immunoprecipitation of V5-tagged CBX7 by pc-L1-1FH is greatly enhanced by coexpression of tagged MOV10 proteins. (B) When overexpressed in the cell culture assay, both CBX7 and PRC1 component CBX8 significantly inhibit L1 retrotransposition, without obvious cell toxicity (C).
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pgen-1002941-g006: Polycomb group (PcG) multiprotein PRC1-like complex component Chromobox homolog 7 (CBX7) associates with the L1-RNP and inhibits retrotransposition.(A) Lanes 1–3: CBX7 binds weakly with the L1 RNP in an RNA-dependent manner. Lanes 4–9: Co-immunoprecipitation of V5-tagged CBX7 by pc-L1-1FH is greatly enhanced by coexpression of tagged MOV10 proteins. (B) When overexpressed in the cell culture assay, both CBX7 and PRC1 component CBX8 significantly inhibit L1 retrotransposition, without obvious cell toxicity (C).

Mentions: In addition to associating with RISC, MOV10 also binds chromobox family protein CBX7 and, to lesser degree, CBX6 and CBX8, components of the Polycomb repressive complex 1 (PRC1), which is involved in maintaining some genes in a transcriptionally repressed state during development. El Messaoudi-Aubert [60] determined that shRNA-mediated knockdown of MOV10 causes up-regulation of INK4a, a known PRC1 target, accompanied by displacement of PRC1 components, histone modification, and chromatin remodeling at the INK4a promoter. We sought to determine by co-IP if Polycomb group proteins also associate with the L1 RNP. Weakly detected in the absence of MOV10, CBX7 was strongly recruited to the L1 RNP when coexpressed with V5- or RFP-tagged MOV10 (Figure 6A; CBX8 bound non-specifically to α-FLAG-agarose making IP results inconclusive; data not shown). CBX7 and CBX8 inhibit cell culture retrotransposition 50 and 60 percent, respectively (Figure 6B), in the absence of overt cellular toxicity (Figure 6C).


MOV10 RNA helicase is a potent inhibitor of retrotransposition in cells.

Goodier JL, Cheung LE, Kazazian HH - PLoS Genet. (2012)

Polycomb group (PcG) multiprotein PRC1-like complex component Chromobox homolog 7 (CBX7) associates with the L1-RNP and inhibits retrotransposition.(A) Lanes 1–3: CBX7 binds weakly with the L1 RNP in an RNA-dependent manner. Lanes 4–9: Co-immunoprecipitation of V5-tagged CBX7 by pc-L1-1FH is greatly enhanced by coexpression of tagged MOV10 proteins. (B) When overexpressed in the cell culture assay, both CBX7 and PRC1 component CBX8 significantly inhibit L1 retrotransposition, without obvious cell toxicity (C).
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Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3475670&req=5

pgen-1002941-g006: Polycomb group (PcG) multiprotein PRC1-like complex component Chromobox homolog 7 (CBX7) associates with the L1-RNP and inhibits retrotransposition.(A) Lanes 1–3: CBX7 binds weakly with the L1 RNP in an RNA-dependent manner. Lanes 4–9: Co-immunoprecipitation of V5-tagged CBX7 by pc-L1-1FH is greatly enhanced by coexpression of tagged MOV10 proteins. (B) When overexpressed in the cell culture assay, both CBX7 and PRC1 component CBX8 significantly inhibit L1 retrotransposition, without obvious cell toxicity (C).
Mentions: In addition to associating with RISC, MOV10 also binds chromobox family protein CBX7 and, to lesser degree, CBX6 and CBX8, components of the Polycomb repressive complex 1 (PRC1), which is involved in maintaining some genes in a transcriptionally repressed state during development. El Messaoudi-Aubert [60] determined that shRNA-mediated knockdown of MOV10 causes up-regulation of INK4a, a known PRC1 target, accompanied by displacement of PRC1 components, histone modification, and chromatin remodeling at the INK4a promoter. We sought to determine by co-IP if Polycomb group proteins also associate with the L1 RNP. Weakly detected in the absence of MOV10, CBX7 was strongly recruited to the L1 RNP when coexpressed with V5- or RFP-tagged MOV10 (Figure 6A; CBX8 bound non-specifically to α-FLAG-agarose making IP results inconclusive; data not shown). CBX7 and CBX8 inhibit cell culture retrotransposition 50 and 60 percent, respectively (Figure 6B), in the absence of overt cellular toxicity (Figure 6C).

Bottom Line: However, unlike MOV10, these other helicases do not strongly inhibit retrotransposition, an activity dependent upon intact helicase domains.Therefore, the host has evolved defense mechanisms to protect against retrotransposition, an arsenal we are only beginning to understand.With homologs in other vertebrates, insects, and plants, MOV10 may represent an ancient and innate form of immunity against both infective viruses and endogenous retroelements.

View Article: PubMed Central - PubMed

Affiliation: McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. jgoodier@jhmi.edu

ABSTRACT
MOV10 protein, a putative RNA helicase and component of the RNA-induced silencing complex (RISC), inhibits retrovirus replication. We show that MOV10 also severely restricts human LINE1 (L1), Alu, and SVA retrotransposons. MOV10 associates with the L1 ribonucleoprotein particle, along with other RNA helicases including DDX5, DHX9, DDX17, DDX21, and DDX39A. However, unlike MOV10, these other helicases do not strongly inhibit retrotransposition, an activity dependent upon intact helicase domains. MOV10 association with retrotransposons is further supported by its colocalization with L1 ORF1 protein in stress granules, by cytoplasmic structures associated with RNA silencing, and by the ability of MOV10 to reduce endogenous and ectopic L1 expression. The majority of the human genome is repetitive DNA, most of which is the detritus of millions of years of accumulated retrotransposition. Retrotransposons remain active mutagens, and their insertion can disrupt gene function. Therefore, the host has evolved defense mechanisms to protect against retrotransposition, an arsenal we are only beginning to understand. With homologs in other vertebrates, insects, and plants, MOV10 may represent an ancient and innate form of immunity against both infective viruses and endogenous retroelements.

Show MeSH
Related in: MedlinePlus