Séminaire virtuel

Three online seminars

Dr. Maxime WERY

16 Juin, 11h

https://u-bordeaux-fr.zoom.us/j/85172548727?pwd=MnhmMTVGK3FHSlhuVGhuaktOblZOZz09

Translation as an unexpected player in the metabolism of long non-coding RNAs

Long non-coding (lnc)RNAs are now recognized as important regulators involved in multiple cellular processes. Surprisingly, although they were initially presumed to be devoid of coding potential, recent works revealed that lncRNAs can be translated. LncRNA-derived micropeptides can have actual intra/extra-cellular roles or be the source of neoantigens driving the immune response, but they might also represent proteins “in progress” throughout evolutionary constraints. However, despite the interest they arouse, the cis- and trans-acting mechanisms controlling the synthesis of these peptides remain poorly characterized. In yeast, we previously showed that the cytoplasmic Xrn1-sensitive lncRNAs are degraded via the Nonsense Mediated mRNA Decay (NMD), a translation-dependent RNA decay pathway, suggesting that translation determines their degradation. During this seminar, I will discuss our latest results showing that the majority of cytoplasmic lncRNAs are actively translated, modulating their cellular abundance and providing an opportunity for the cell to produce novel peptides. We propose that translation of lncRNAs could expose lncRNA-derived micropeptides to the natural selection, reflecting the ongoing evolutionary process of de novo gene birth, while NMD would prevent the accumulation of the transcript they originate from.

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Prof. Dr. Mark Helm

12 Avril, 11h

RNA modifications: how to find and how to use

RNA modifications have gained the attention of a larger audience about a decade ago, when the then minted term “epitranscriptomics” summarized the effect of modifications in the transcriptome. That development, largely sustained by new detection technology, has maintained its momentum up to date. Yet earlier, RNA modification research has revealed a function of mammalian RNA modifications as a label for “self”, in order to pass molecular inspection by components of the innnate immunesystem. These properties were the basis for the recent development of highly modified, synthetic mRNAs used as antiviral vaccines. I am presenting results on the synthesis of mRNA containing single modifications with immune-evading properties, with emphasis on the methods used for characterizing their modifications content.

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Prof. Dr. Martin Jinek

3 mars, 11h

Molecular mechanisms of CRISPR-associated genome editor nucleases and transposons

Abstract:
RNA-guided effector nucleases associated with prokaryotic CRISPR-Cas genome defense systems have been repurposed as powerful tools for precision genome editing in eukaryotic cells and organisms. In previous studies, my laboratory revealed how the genome editor nucleases Cas9 and Cas12 use guide RNAs to recognize and cleave their DNA targets. Despite their intrinsically high specificity, these enzymes can nevertheless cleave mismatched off-target DNA sequences, which presents a concern for their therapeutic use. By determining multiple structures of Cas9 in complexes with off-target substrates, we now show that its off-target activity is primarily enabled by the formation of non-canonical base pairs and preservation of base stacking within the guide RNA–off-target heteroduplex. These findings provide a structural rationale for the off-target activity of Cas9 and facilitate engineering of ultraspecific guide RNA designs for clinical applications.
Although the canonical function of CRISPR-Cas systems is to provide adaptive immunity against mobile genetic elements, some CRISPR systems have been adopted by Tn7-like transposons to mediate RNA-guided DNA transposition. Our recent structural work focuses on the type V CRISPR-associated pseudonuclease Cas12k and its transposase partner TnsC, showing how these proteins recognize and remodel target DNA. These studies advance our mechanistic understanding of CRISPR-associated transposons and will guide their development of as programmable site-specific gene insertion tools.

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