The Mediator co-activator complex regulates Ty1 retromobility by controlling the balance between Ty1i and Ty1 promoters

Abstract

The Ty1 retrotransposons present in the genome of Saccharomyces cerevisiae belong to the large class of mobile genetic elements that replicate via an RNA intermediary and constitute a significant portion of most eukaryotic genomes. The retromobility of Ty1 is regulated by numerous host factors, including several subunits of the Mediator transcriptional co-activator complex. In spite of its known function in the nucleus, previous studies have implicated Mediator in the regulation of post-translational steps in Ty1 retromobility. To resolve this paradox, we systematically examined the effects of deleting non-essential Mediator subunits on the frequency of Ty1 retromobility and levels of retromobility intermediates. Our findings reveal that loss of distinct Mediator subunits alters Ty1 retromobility positively or negatively over a >10,000-fold range by regulating the ratio of an internal transcript, Ty1i, to the genomic Ty1 transcript. Ty1i RNA encodes a dominant negative inhibitor of Ty1 retromobility that blocks virus-like particle maturation and cDNA synthesis. These results resolve the conundrum of Mediator exerting sweeping control of Ty1 retromobility with only minor effects on the levels of Ty1 genomic RNA and the capsid protein, Gag. Since the majority of characterized intrinsic and extrinsic regulators of Ty1 retromobility do not appear to effect genomic Ty1 RNA levels, Mediator could play a central role in integrating signals that influence Ty1i expression to modulate retromobility.

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

“…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.…”

Diverse transposable element landscapes in pathogenic and nonpathogenic yeast models: the value of a comparative perspective

“…This truncated Gag strongly inhibits Ty1 retrotransposition by interacting with the normal Gag protein to decrease VLP assembly and alter VLP structure [195,196]. Regulation of Ty1 by some ribosome biogenesis proteins and the Mediator transcriptional co-activator occurs at least in part by altering the expression of this truncated Gag protein [197,198]. Ty1 self-restriction may have evolved as a means of Ty1 stably remaining in an organism that lacks genome-wide small RNA-based repressive mechanisms to limit potentially deleterious unrestricted retrotransposition.…”

Movements of Ancient Human Endogenous Retroviruses Detected in SOX2-Expressing Cells

“…For example, APOBEC3F, a restriction factor in cell-free HERV-K infection ( 9 ), may inhibit HERV-K retrotransposition during reverse transcription. In the yeast Saccharomyces cerevisiae , Ty1 LTR retrotransposon Gag forms virus-like particles as retrosomes for reverse transcription ( 53 ). APOBEC3G interacts with Ty1 Gag in retrosomes and restricts Ty1 retrotransposition ( 54 , 55 ).…”

“…APOBEC3G interacts with Ty1 Gag in retrosomes and restricts Ty1 retrotransposition ( 54 , 55 ). However, it is unknown whether HERV-K Gag forms a retrosome similar to Ty1 ( 53 ) or whether APOBEC3F can access the HERV-K genome in the retrosome. In the future, the mechanism of HERV-K retrotransposition should be clarified.…”