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Monday 19 Novembre at 11h: Pascale Lesage, Institut Universitaire d’Hématologie, Hôpital St-Louis, Paris. "Molecular mechanisms and regulation of Ty1 retrotransposon integration site selection"

Abstract (...)

Abstract Retroelements (i.e. retroviruses and retrotransposons) replicate by reverse transcription of their RNA genome into a cDNA that is stably integrated into the host-cell genome by their own integrase (IN). Integration does not occur randomly in vivo, revealing a retroelement-specific pattern of preferred sites, which depends mostly of INs interaction with cellular factors that tether integration to specific sites. Important understandings on the mechanisms by which these factors interact with IN and contribute to the integration process have been gained by studying yeast Ty1 LTR-retrotransposon. Ty1 preferentially integrates upstream of RNA polymerase III (Pol III)-transcribed genes. We identified an interaction between Ty1 IN and the Pol III subunit AC40, and demonstrated that AC40 is a predominant determinant of Ty1 integration targeting at Pol III-transcribed genes. Lack of an AC40/IN interaction dramatically alters Ty1 integration profile, leading to a redistribution of Ty1 insertions in the genome, mainly to chromosome ends. Ty1 targeting mechanism within individually non-essential Pol III genes provides safe landing sites that prevent deleterious consequences on cell fitness. Yet, McClintock had proposed that one role of transposable elements may be to favor genome-wide changes in response to environmental challenge. In that respect, subtelomeric regions contain genes involved in response to environmental challenges, so that Ty1 integration in these regions could facilitate evolution. To further understand the role of Pol III in Ty1 integration, we are currently investigating the amino acids in IN and AC40 that are involved in AC40/IN interaction. In collaboration with J. Acker (I2BC, CEA), we have also performed proteomic approaches to identify IN cofactors in vivo. On the other hand, we are exploring high-throughput sequencing data of de novo Ty1 insertion events in the absence of AC40/IN interaction and testing whether identified associations between Ty1 insertions and specific chromosomal features or histone modifications are consistent with a secondary target site preference of Ty1 at subtelomeres.
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