A Role for the Mre11-Rad50-Xrs2 Complex in Gene Expression and Chromosome Organization

Forey, Romain; Barthe, Antoine; Tittel-Elmer, Mireille; Wéry, Maxime; Barrault, Marie-Bénédicte; Ducrot, Cécile; Seeber, Andrew; Krietenstein, Nils; Szachnowski, Ugo; Skrzypczak, Magdalena; Ginalski, Krzysztof; Rowicka, Maga; Cobb, Jennifer A.; Rando, Oliver J.; Soutourina, Julie; Werner, Michel; Dubrana, Karine; Gasser, Susan M.; Morillon, Antonin; Pasero, Philippe; Lengronne, Armelle; Poli, Jérôme

doi:10.1016/j.molcel.2020.11.010

“…In this respect, it is striking that tDNA loci, which are adjacent to most Ty1 sequences in the genome due to Ty1 preferential integration close to Pol III-transcribed genes (reviewed in [85]), undergo cell-cycle dependent relocalization to the NPCs [40], and that a number of transcription factors, including the bona fide Ty1 activators Gcn4 and Ste12, are sufficient to promote the NPC association of their target sequences [86]. At this position, Ty1 elements may integrate the signals from various NPC-associated factors, including the Mediator co-activator complex [14], which also acts at Ty1 promoters [87], or specific partners of the Nup84 complex, as suggested by the co-evolution scored between Ty1 elements and NUP84 sequences in Saccharomyces yeasts [88]. In the future, genome-wide and imaging analysis investigating the position of Ty1 elements in the nucleus will be instrumental to decipher the relationships between the expression of transposable elements and their localization with respect to NPCs.…”

Section: Discussionmentioning

confidence: 99%

“…Beyond their canonical role in the selective transport of proteins and RNAs, NPCs have also emerged as key platforms for the three-dimensional organization of the genome, thereby impacting the regulation of gene expression and the maintenance of genetic integrity (reviewed in [3][4][5]). Genome-wide approaches, together with the live imaging of individually-tagged loci, have revealed that nucleoporins associate mostly with transcriptionally-active genes, but also with repressed regions and chromatin boundaries, from yeasts to metazoans [6][7][8][9][10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

“…Beyond their canonical role in the selective transport of proteins and RNAs, NPCs have also emerged as key platforms for the three-dimensional organization of the genome, thereby impacting the regulation of gene expression and the maintenance of genetic integrity (reviewed in [3–5]). Genome-wide approaches, together with the live imaging of individually-tagged loci, have revealed that nucleoporins associate mostly with transcriptionally-active genes, but also with repressed regions and chromatin boundaries, from yeasts to metazoans [6–14]. While a subset of nucleoporins can bind their target sequences away from the NPC [15–17], these interactions typically occur at the nuclear envelope, as exemplified by the well-described recruitment of induced genes to the pores in budding yeast [18–21].…”

Section: Introductionmentioning

confidence: 99%

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

Bonnet

¹

,

Chaput

²

,

Palancade

³

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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“…Immunoprecipitations were performed as previously described (Forey et al, 2021) by lysing 40 to 50 OD600 units of exponential phase cultures. After sonication, clarification and benzonase treatment (250 u/1 mg protein, SIGMA E1014-5KU) extracts were incubated 1h at 4°C with 50 µL magnetic beads (Dynabeads M-280 sheep anti-mouse IgG ,invitrogen 11202D) coated with anti-GFP antibodies (Roche ref:11814460001).…”

Section: Co-immunoprecipitation (Co-ip)mentioning

confidence: 99%

Sir3 Heterochromatin Protein Promotes NHEJ by Direct Inhibition of Sae2

Bordelet

¹

,

Costa

²

,

Brocas

³

et al. 2021

Preprint

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0

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Heterochromatin is a conserved feature of eukaryotic chromosomes, with central roles in gene expression regulation and maintenance of genome stability. How DNA repair occurs in heterochromatin remains poorly described. In Saccharomyces cerevisiae, the Silent Information Regulator (SIR) complex assembles heterochromatin-like chromatin at subtelomeres. SIR-mediated repressive chromatin limits double strand break (DSB) resection protecting damaged chromosome ends during HR. As resection initiation marks the cross-road between repair by non-homologous end joining (NHEJ) or HR, we asked whether SIR-mediated heterochromatin regulates NHEJ. We show that SIRs promotes NHEJ through two pathways, one depending on repressive chromatin assembly, and the other relying on Sir3 in a manner that is independent of its heterochromatin-promoting function. Sir3 is a potent inhibitor of Sae2-dependent MRX functions. Sir3 physically interacts with Sae2 and this interaction impairs Sae2 interaction with MRX. As a consequence, Sir3 limits Mre11-mediated resection, delays MRX removal from DSB ends and promotes NHEJ.

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“…Beyond their canonical role in the selective transport of proteins and RNAs, NPCs have also emerged as key platforms for the three-dimensional organization of the genome, thereby impacting the regulation of gene expression and the maintenance of genetic integrity (reviewed in [3][4][5]). Genome-wide approaches, together with the live imaging of individuallytagged loci, have revealed that nucleoporins associate mostly with transcriptionally-active genes, but also with repressed regions and chromatin boundaries, from yeasts to metazoans [6][7][8][9][10][11][12][13][14]. While a subset of nucleoporins can bind their target sequences away from the NPC [15][16][17], these interactions typically occur at the nuclear envelope, as exemplified by the welldescribed recruitment of induced genes to the pores in budding yeast [18][19][20][21].…”

Section: Introductionmentioning

confidence: 99%

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

Bonnet

¹

,

Chaput

²

,

Palmic

³

et al. 2021

PLoS Genet

4

0

View full text Add to dashboard Cite

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 study expands our understanding of the complex interactions between retrotransposons and the NPC, and highlights the importance for the cells to keep retrotransposons under tight transcriptional control.

show abstract

A Role for the Mre11-Rad50-Xrs2 Complex in Gene Expression and Chromosome Organization

Cited by 18 publications

References 95 publications

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

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

Sir3 Heterochromatin Protein Promotes NHEJ by Direct Inhibition of Sae2

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

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