Compartment-specific and ELAVL1-coordinated regulation of intronic polyadenylation isoforms by doxorubicin.

Intronic polyadenylation (IPA) isoforms, which contain alternative last exons, are widely regulated in various biological processes and by many factors. However, little is known about their cytoplasmic regulation and translational status. In this study, we provide the first evidence that the genome-wide patterns of IPA isoform regulation during a biological process can be very distinct between the transcriptome and translatome, and between the nucleus and cytosol. Indeed, by 3'-seq analyses on breast cancer cells, we show that the genotoxic anticancer drug, doxorubicin, preferentially down-regulates the IPA to the last-exon (IPA:LE) isoform ratio in whole cells (as previously reported) but preferentially up-regulates it in polysomes. We further show that in nuclei, doxorubicin almost exclusively down-regulates the IPA:LE ratio, whereas in the cytosol, it preferentially up-regulates the isoform ratio, as in polysomes. Then, focusing on IPA isoforms that are up-regulated by doxorubicin in the cytosol and highly translated (up-regulated and/or abundant in polysomes), we identify several IPA isoforms that promote cell survival to doxorubicin. Mechanistically, by using an original approach of condition- and compartment-specific CLIP-seq (CCS-iCLIP) to analyze ELAVL1-RNA interactions in the nucleus and cytosol in the presence and absence of doxorubicin, as well as 3'-seq analyses upon ELAVL1 depletion, we show that the RNA-binding protein ELAVL1 mediates both nuclear down-regulation and cytosolic up-regulation of the IPA:LE isoform ratio in distinct sets of genes in response to doxorubicin. Altogether, these findings reveal differential regulation of the IPA:LE isoform ratio across subcellular compartments during drug response and its coordination by an RNA-binding protein.

[Management of SAH]. / Prise en charge de la HSA.

Every year, the neurosurgical intensive care unit at Grenoble's university hospital (CHU) receives a large number of cerebrovascular patients. Data collected in the department during 2023 show that subarachnoid hemorrhage (SAH) is one of the most frequent causes of the pathologies treated. In this article, we focus on the appropriate course of action.

Access to a stabilized i-motif DNA structure through four successive ligation reactions on a cyclopeptide scaffold.

i-Motifs are largely underexplored tetraplex nucleic acid structures which have been suggested to perform essential biological functions and might constitute future therapeutic targets. i-Motifs generally require acidic conditions to fold in vitro, a particularity which significantly complicates the use of native i-motif forming sequences for interaction studies with potential ligands and biological components (e.g. proteins). In this context, we report herein on the assembly of a peptide-DNA conjugate capable of folding at room temperature into a stable i-motif structure at neutral pH. To achieve the controlled assembly of the i-motif forming conjugate, we developed a new synthetic pathway of four successive orthogonal ligation reactions between bifunctional C-rich DNA strands and a tetrafunctional cyclopeptide scaffold.

Assessment of presumed small-molecule ligands of telomeric i-DNA by biolayer interferometry (BLI).

Biolayer interferometry (BLI) and circular dichroism (CD) spectroscopy were used to investigate the interaction between previously reported i-motif DNA (i-DNA) ligands and folded or unfolded i-DNA in acidic (pH 5.5) and near-neutral (pH 6.5) conditions. We observed that although several ligands, in particular macrocyclic bis-acridine (BisA) and pyridostatin (PDS), showed good affinities for the telomeric i-motif forming sequence, none of the ligands displayed selective interactions with the i-DNA structure nor was able to promote its formation.

At the crossroads of RNA biology, genome integrity and cancer.

This article is the synthesis of the scientific presentations that took place during two international courses at Institute Curie, one on post-transcriptional gene regulation and the other on genome instability and human disease, that were joined together in their 2021 edition. This joined course brought together the knowledge on RNA metabolism and the maintenance of genome stability.

Agents' pivotality and reward fairness modulate sense of agency in cooperative joint action.

The sense of agency (SoA) experienced in joint action is an essential subjective dimension of human cooperativeness, but we still know little about the specific factors that contribute to its emergence or alteration. In the present study, dyads of participants were instructed to coordinate their key presses to move a cursor up to a specific target (i.e., to achieve a common goal). We applied random deviations on the cursor's trajectory to manipulate the motor fluency of the joint action, while the agents' motor roles were either balanced (i.e., equivalent) or unbalanced (i.e., one agent contributed more than the other), making the agents more or less pivotal to the joint action. Then, the final outcomes were shared equally, fairly (i.e., reflecting individual motor contributions) or arbitrarily in an all-or-none fashion, between the co-agents. Self and joint SoA were measured through self-reports about feeling of control, that is, using judgment of (felt) control (JoC), and electrodermal activity was recorded during the whole motor task. We observed that self and joint JoC were reduced in the case of low motor fluency, pointing out the importance of sensorimotor cues for both I- and we-modes. Moreover, while self JoC was reduced in the low pivotality condition (i.e., low motor role), joint JoC was significantly enhanced when agents' roles and rewards were symmetrical (i.e. equal). Skin conductance responses to rewards were impacted by the way outcomes were shared between partners (i.e., fairly, equally or arbitrarily) but not by the individual gains, which demonstrates the sensitivity of low-level physiological reactions to external signs of fairness. Skin conductance level was also reduced in the fair context, where rewards were shared according to individual motor contributions, relative to the all-or-none context, which could mirror the feeling of effective responsibility and control over actions' outcomes.