Mobilization of LINE-1 retrotransposons is restricted by Tex19.1 in mouse embryonic stem cells

MacLennan, Marie; García-Cañadas, Marta; Reichmann, Judith; Khazina, Elena; Wagner, Gerd K.; Playfoot, Christopher J; Salvador-Palomeque, Carmen; Mann, Abigail; Peressini, Paula; Sánchez, Laura; Dobie, Karen; Read, David; Hung, Chao-Chun; Eskeland, Ragnhild; Meehan, Richard R.; Weichenrieder, Oliver; García‐Pérez, José L.; Adams, Ian R.

doi:10.7554/elife.26152

Cited by 47 publications

(70 citation statements)

References 128 publications

(241 reference statements)

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“…The identification of cul-6/ cullin and substrate-specific adaptors of a E3 ubiquitin ligase complex suggests a role for ubiquitylation in the response to LTR retrotransposons in C. elegans. In mouse, LINE-1 retrotransposon mobilization is restricted by ubiquitylation of a retrotransposon-encoded protein by an E3 ubiquitin ligase, resulting in protein degradation in mouse embryonic stem cells (44).…”

Section: Discussionmentioning

confidence: 99%

Caenorhabditis elegans ADAR editing and the ERI-6/7/MOV10 RNAi pathway silence endogenous viral elements and LTR retrotransposons

Fischer

Ruvkun

2020

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

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Endogenous retroviruses and long terminal repeat (LTR) retrotransposons are mobile genetic elements that are closely related to retroviruses. Desilenced endogenous retroviruses are associated with human autoimmune disorders and neurodegenerative diseases. Caenorhabditis elegans and related Caenorhabditis spp. contain LTR retrotransposons and, as described here, numerous integrated viral genes including viral envelope genes that are part of LTR retrotransposons. We found that both LTR retrotransposons and endogenous viral elements are silenced by ADARs [adenosine deaminases acting on double-stranded RNA (dsRNA)] together with the endogenous RNA interference (RNAi) factor ERI-6/7, a homolog of MOV10 helicase, a retrotransposon and retrovirus restriction factor in human. siRNAs corresponding to integrated viral genes and LTR retrotransposons, but not to DNA transposons, are dependent on the ADARs and ERI-6/7. siRNAs corresponding to palindromic repeats are independent of the ADARs and ERI-6/7, and are in fact increased in adarand eri-6/7-defective mutants because of an antiviral RNAi response to dsRNA. Silencing of LTR retrotransposons is dependent on downstream RNAi factors and P granule components but is independent of the viral sensor DRH-1/ RIG-I and the nuclear Argonaute NRDE-3. The activation of retrotransposons in the ADAR-and ERI-6/7/MOV10-defective mutant is associated with the induction of the unfolded protein response (UPR), a common response to viral infection. The overlap between genes induced upon viral infection and infection with intracellular pathogens and genes coexpressed with retrotransposons suggests that there is a common response to different types of foreign elements that includes a response to proteotoxicity presumably caused by the burden of replicating pathogens and expressed retrotransposons.RNA interference | ADAR | retrotransposon | RNA silencing

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Section: Discussionmentioning

confidence: 99%

Caenorhabditis elegans ADAR editing and the ERI-6/7/MOV10 RNAi pathway silence endogenous viral elements and LTR retrotransposons

Fischer

Ruvkun

2020

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

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“…The identification of cul-6/cullin and substrate-specific adaptors of a E3 ubiquitin ligase complex suggests a role for ubiquitylation in the response to LTR retrotransposons in C. elegans . In mouse, LINE-1 retrotransposon mobilization is restricted by ubiquitylation of a retrotransposon-encoded protein by an E3 ubiquitin ligase, resulting in protein degradation in mouse embryonic stem cells (39)…”

Section: Discussionmentioning

confidence: 99%

Caenorhabditis elegans ADAR editing and the ERI-6/7/MOV10 RNAi pathway silence endogenous viral elements and LTR retrotransposons

Fischer

Ruvkun

2019

Preprint

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18Endogenous retroviruses and LTR retrotransposons are mobile genetic elements that 19 are closely related to retroviruses. Desilenced endogenous retroviruses are associated 20 with human autoimmune disorders and neurodegenerative diseases. C. elegans and 21 related Caenorhabdites contain LTR retrotransposons and, as described here, 22 numerous integrated viral genes including viral envelope genes that are part of LTR 23 retrotransposons. We found that both LTR retrotransposons and endogenous viral 24 elements are silenced by ADARs (adenosine deaminases acting on double-stranded 25 RNA (dsRNA)) together with the endogenous RNAi factor ERI-6/7, a homolog of Mov10 26 helicase, a retrotransposon and retrovirus restriction factor in human. siRNAs 27 Transposons can have profound effects on cellular function such as disruption of gene 53 function by transposon insertion, cell death as a consequence of transposon-induced 54 double stranded breaks, and genomic rearrangements caused by homologous 55 recombination between repeat elements. Retrotransposons and endogenous 56 retroviruses may affect cellular function through overexpression of toxic proteins or the 57 activity of retroviral proteins on endogenous sequences. Palindromic repeat elements 58 such as those formed by adjacent but inverted insertion of vertebrate Alu elements 59 into genes can cause the accumulation of dsRNA. 60 Many RNA viruses replicate via a dsRNA intermediate, which is detected to 61 trigger an interferon-based antiviral response in mammals and an RNA interference 62 response in invertebrates. To avoid an anti-viral response to endogenous palindromic 63 dsRNAs when in fact there is no viral infection, ADARs edit adenosines to inosines in 64 endogenous dsRNA destabilizing the RNA duplex and thus preventing recognition by 65

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“…These findings confirm our and others previous observations that Tex19.1 mRNA is a DAZL target 19, 27 . TEX19.1 protein accumulates during oocyte maturation and data in the testis indicate that this protein may be involved in the regulation of transposon expression 28, 29, 30 . Similarly, DAZL regulation of Btg4 mRNA translation has been reported by others 31, 32, 33 .…”

Section: Discussionmentioning

confidence: 99%

The RNA binding protein DAZL functions as repressor and activator of maternal mRNA translation during oocyte maturation

Yang

Rajkovic

Daldello

et al. 2019

Preprint

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28Deleted in azoospermia like (DAZL) is an RNA-binding protein playing critical function during 29 gamete development. In fully-grown oocytes, DAZL protein is detected in prophase and levels 30 increase four to five fold during reentry into the meiotic cell cycle. Here, we have investigated the 31 functional significance of this DAZL accumulation in maturing oocytes. Oocyte depletion of DAZL 32 prevents progression to MII. This maturation block is associated with widespread disruption in the 33 pattern of maternal transcripts loading on ribosomes and their translation measured using a 34RiboTag IP/RNASeq or qPCR strategy. In addition to decreased ribosome loading of a subset of 35 transcripts, we found that DAZL depletion causes also translational activation of distinct subset of 36 mRNAs. DAZL binds to mRNAs whose translation is both repressed and activated during oocyte 37 maturation. Unexpectedly, DAZL depletion also causes increased ribosome loading of a subset 38 of mRNAs in quiescent GV-arrested oocytes. This dual role of repression and activation is 39 recapitulated by using YFP reporters including the 3'UTR of DAZL targets. Injection of 40 recombinant DAZL protein in DAZL-depleted oocytes rescues the translation of these targets as 41 well as maturation to MII. Mutagenesis of putative DAZL-binding sites in these candidate mRNAs 42 mimics the effect of DAZL depletion. These findings demonstrate that DAZL regulates translation 43 of maternal mRNAs in mature oocytes, functioning both as translational repressor and activator. 44 45 46

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Mobilization of LINE-1 retrotransposons is restricted by Tex19.1 in mouse embryonic stem cells

Cited by 47 publications

References 128 publications

Caenorhabditis elegans ADAR editing and the ERI-6/7/MOV10 RNAi pathway silence endogenous viral elements and LTR retrotransposons

Caenorhabditis elegans ADAR editing and the ERI-6/7/MOV10 RNAi pathway silence endogenous viral elements and LTR retrotransposons

Caenorhabditis elegans ADAR editing and the ERI-6/7/MOV10 RNAi pathway silence endogenous viral elements and LTR retrotransposons

The RNA binding protein DAZL functions as repressor and activator of maternal mRNA translation during oocyte maturation

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