A small targeting domain in Ty1 integrase is sufficient to direct retrotransposon integration upstream of tRNA genes

Asif-Laidin, Amna; Conesa, Christine; Bonnet, Amandine; Grison, Camille; Adhya, Indranil; Menouni, Rachid; Fayol, Hélène; Palmic, Noé; Acker, Joël; Lesage, Pascale

doi:10.15252/embj.2019104337

Cited by 25 publications

(58 citation statements)

References 95 publications

(156 reference statements)

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“…TEs have maximized their chance of propagation because of an accurate control of integration events specifically targeting non-deleterious regions of the genome. This is the case for Ty1, which targets its integration upstream of Pol III-transcribed genes through direct interactions between IN and Pol III (11,12). The architecture that we reveal with our SAXS model and Interestingly, the folded N-terminal half and the intrinsically disordered C-terminal regions of Ty1 IN appear to act independently.…”

Section: Sso7d-in Shows a Behavior In Terms Of Integration And Disintegration Activities Similarmentioning

confidence: 51%

“…The Ty1 mRNA is then reverse transcribed by RT into a linear doublestranded DNA copy (cDNA). IN binds to the cDNA to form the pre-integration complex, which migrates into the nucleus where the cDNA is integrated into the host genome (6), preferentially upstream of Pol III-transcribed genes (7)(8)(9)(10) through a direct interaction between IN and Pol III (11,12). Previous studies suggest that, like retroviruses, Ty1 integration process is carried out by complexes composed of multiple copies of IN assembled on the LTR DNA ends, commonly called intasomes (13,14).…”

Section: Introductionmentioning

confidence: 99%

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Ty1 integrase is composed of an active N-terminal domain and a large disordered C-terminal module dispensable for its activity in vitro

Nguyen

Conesa²,

Rabut³

et al. 2021

Journal of Biological Chemistry

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Section: Sso7d-in Shows a Behavior In Terms Of Integration And Disintegration Activities Similarmentioning

confidence: 51%

Section: Introductionmentioning

confidence: 99%

Ty1 integrase is composed of an active N-terminal domain and a large disordered C-terminal module dispensable for its activity in vitro

Nguyen

Conesa²,

Rabut³

et al. 2021

Journal of Biological Chemistry

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“…Ty1 mobility was measured as previously described in [91]. Briefly, four independent clones of strains harboring a Ty1-his3AI chromosomal reporter were grown to saturation for 24h at 30°C in liquid YPD.…”

Section: Retrotransposition Assaymentioning

confidence: 99%

A nuclear pore sub-complex restricts the propagation of Ty retrotransposons by limiting their transcription

Bonnet

Chaput

Palancade

et al. 2021

Preprint

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Beyond their canonical function in nucleocytoplasmic exchanges, nuclear pore complexes (NPCs) regulate the expression of protein-coding genes. Here, we have implemented transcriptomic and molecular methods to specifically address the impact of the NPC on retroelements, which are present in multiple copies in genomes. We report a novel function for the Nup84 complex, a core NPC building block, in specifically restricting the transcription of LTR-retrotransposons in yeast. Nup84 complex-dependent repression impacts both Copia and Gypsy Ty LTR-retrotransposons, all over the S. cerevisiae genome. Mechanistically, the Nup84 complex restricts the transcription of Ty1, the most active yeast retrotransposon, through the tethering of the SUMO-deconjugating enzyme Ulp1 to NPCs. Strikingly, the modest accumulation of Ty1 RNAs caused by Nup84 complex loss-of-function is sufficient to trigger an important increase of Ty1 cDNA levels, resulting in massive Ty1 retrotransposition. Altogether, our studies expand our understanding of the complex interactions between retrotransposons and the NPC, and highlight the importance for the cells to keep retrotransposon under tight transcriptional control.AUTHOR SUMMARYRetroelements, which replicate by reverse transcription of their RNA into a cDNA that is integrated into the host genetic material, play an important role in the plasticity of eukaryotic genomes. The study of yeast retrotransposons has led to the identification of host factors that limit retroelement mobility, including components of the nuclear pore complex (NPC), most of them still awaiting mechanistic characterization. Here, we investigated the contribution of the Nup84 complex, a core NPC scaffold, to retrotransposon biology in budding yeast. Our findings uncover that the Nup84 complex restricts the transcription of phylogenetically-distinct Ty retroelements. By focusing on Ty1 retrotransposons, we provide evidence that repression by the Nup84 complex depends on the maintenance at the NPC of the SUMO-protease Ulp1, an essential enzyme of the SUMO pathway with multiple targets in the transcription machinery. We finally show that this transcriptional control is critical for genome dynamics, since a small increase in the accumulation of Ty1 RNAs leads to massive retrotransposition. Our data reveal that although relatively abundant, Ty transcripts are limiting for retrotransposition, underscoring the importance of a tight control of their expression. They also characterize a new non-canonical function of NPCs, confirming their connection with genome expression and stability.

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“…Furthermore, the comparison of the two structures reveals that the Ty3 intasome and Pol III would occupy nearly the exact same position, thus providing mechanistic evidence that Pol III transcription and Ty3 integration are mutually exclusive, as previously postulated by studies suggesting competition between the two processes 48,63 . Unlike Ty3, Ty1 retrotransposon integrates at nucleosomal DNA and requires a physical association with the Pol III enzyme 13,14,64 rationalising why Ty3 and Ty1 do not compete for the same integration sites.…”

Section: Ty3 Integration and Rna Pol III Transcription Are Mutually Exclusivementioning

confidence: 99%

Structural basis of Ty3 retrotransposon integration at RNA Polymerase III-transcribed genes

Abascal-Palacios

Jochem

Pla‐Prats

et al. 2021

Preprint

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Retrotransposons are endogenous elements that have the ability to mobilise their DNA and integrate at different locations in the host genome. In budding yeast, the Ty3 retrotransposon integrates with an exquisite specificity in a narrow window upstream of RNA Polymerase III-transcribed genes, such as the genes of transfer RNAs, representing a paradigm for specific targeted integration. Here we present the cryo-EM reconstruction at 4.0 Å-resolution of an active Ty3 strand-transfer complex (Ty3 intasome) caught in the act of integrating onto a specific tRNA gene bound to the RNA Polymerase III general transcription factor TFIIIB, which is required for Ty3 specific targeting. The structure unravels the molecular mechanisms underlying Ty3 integration specificity at RNA Polymerase III-transcribed genes and sheds light into the architecture of a retrotransposon integration machinery during the process of strand transfer at a genomic locus. The Ty3 intasome establishes contacts with a region of the TATA-binding protein (TBP), a subunit of TFIIIB, which is blocked by the ubiquitous transcription regulator negative cofactor 2 (NC2) in RNA Pol II-transcribed genes. A previously unrecognised chromodomain of the Ty3 integrase mediates non-canonical interactions with TFIIIB and the tRNA gene itself, defining with extreme precision the position of the integration site. Surprisingly, Ty3 retrotransposon tethering to TFIIIB topologically resembles LEDGF/p75 transcription factor targeting by HIV retrovirus, highlighting mechanisms of convergent evolution by unrelated mobile elements and host organisms. The Ty3 intasome-TFIIIB-tRNA promoter complex presented here represents a detailed molecular snapshot of a general transcription factor's co-option by a mobile element, resulting in harmless integration into the host genome.

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A small targeting domain in Ty1 integrase is sufficient to direct retrotransposon integration upstream of tRNA genes

Cited by 25 publications

References 95 publications

Ty1 integrase is composed of an active N-terminal domain and a large disordered C-terminal module dispensable for its activity in vitro

Ty1 integrase is composed of an active N-terminal domain and a large disordered C-terminal module dispensable for its activity in vitro

A nuclear pore sub-complex restricts the propagation of Ty retrotransposons by limiting their transcription

Structural basis of Ty3 retrotransposon integration at RNA Polymerase III-transcribed genes

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