Transcription as a Threat to Genome Integrity

Genomes undergo different types of sporadic alterations, including DNA damage, point mutations, and genome rearrangements, that constitute the basis for evolution. However, these changes may occur at high levels as a result of cell pathology and trigger genome instability, a hallmark of cancer and a number of genetic diseases. In the last two decades, evidence has accumulated that transcription constitutes an important natural source of DNA metabolic errors that can compromise the integrity of the genome. Transcription can create the conditions for high levels of mutations and recombination by its ability to open the DNA structure and remodel chromatin, making it more accessible to DNA insulting agents, and by its ability to become a barrier to DNA replication. Here we review the molecular basis of such events from a mechanistic perspective with particular emphasis on the role of transcription as a genome instability determinant

Gene gating at nuclear pores prevents the formation of R loops

Transcription is an important source of genetic variability. A large amount of transcription-associated genome variation arises from the unscheduled formation of R loops. We have recently found that physical proximity of chromatin to nuclear pores prevents the formation of pathological R loops during transcription. Our study opens new perspectives to understand genome stability as a function of nuclear location

Keith Haring et l’héritage de la peinture américaine du XXème siècle

Si Keith Haring est bien reconnu comme l’un des pionniers du street art, les sources de son travail sont trop souvent réduites au Pop art. Loin de se poser en rupture avec les pratiques préexistantes, le street art tel que conçu par Haring reprend les codes et la raison d’être des grandes tendances picturales du XXème siècle aux Etats-Unis. Le street artist cite d’ailleurs comme influence majeure Robert Henri, chef de file de l’école de la poubelle, un courant qui annonce la démocratisation de l’art américain. A travers la résonance des courants artistiques du XXème siècle dans la pratique de Keith Haring, cette étude aura pour objectif de replacer les origines du mouvement street art au coeur d’une tradition américaine centrée sur le lien entre l’artiste et son public et la notion d’espace artistique. Ce nouvel éclairage permettra de redéfinir les contours du street art en gardant à l’esprit la question du radicalisme de ce mouvement qui tend à s’institutionnaliser.Although Keith Haring is seen as a pioneer in the street art movement, the sources of his work are often limited to Pop Art. Yet, Haring’s street art practices do not depart from the past trends retaining instead many key aspects and principles at the core of 20th century American art. As a matter of fact, the street artist acknowledges Ashcan school leader Robert Henri — who started a trend said to be the first democratic American art—as his main influence. By observing to what extent Haring’s art echoes the preexisting American artistic values, this study will provide a new historic context to the origins of street art. It will also lead to reexamine the question of street art’s radicalism, considering the gradual evolution of its paradoxical acceptance into museums

« The Great Figure » : déchiffrer la stase dynamique opérée par William Carlos Williams et Charles Demuth

Dans son hommage pictural à « The Great Figure » (1921) composé par son ami William Carlos Williams, Charles Demuth magnifie ce qui est fondamental dans le poème : la stase du regard au cœur du mouvement et du chaos. Si le terme « moving » est en position centrale parmi les treize vers libres de Williams, c’est bien parce que le poème marque l’expérience de « l’immobilité vive » (Barthes 81). Ainsi, la tâche du peintre devant opérer avec l’inertie picturale pour en faire une translation en peinture n’en est que plus complexe. Mais par son recours aux modes futuristes et cubistes, Charles Demuth parvient dans I Saw the Figure 5 in Gold (1928) à transcender la fixité de l’image pour re-présenter cette stase dynamique. Si le 5, ce détail qui attire inopinément l’attention, est « ce hasard qui point » (Barthes 48) le poète dans « The Great Figure », il correspond encore au punctum dans la toile en ce « qu’il part de la scène, comme une flèche, et vient percer » le spectateur (Barthes 49). Prenant pour appui les travaux de Roland Barthes concernant l’immobilité vive, cette étude aura pour objet d’observer les effets communs entre le poème imagiste et la peinture précisionniste, non pas pour leur assigner un nouveau sens, mais pour analyser la nouvelle temporalité insufflée par cette stase dynamique.This paper examines how William Carlos Williams and Charles Demuth are linked through the impression of “intense immobility” (Barthes 81) they respectively develop in the poem “The Great Figure” (1921) and the painting I Saw the Figure 5 in Gold (1928). Indeed, the notion of movement is predominant in the one-sentence poem as evidenced by the central line “moving”. Charles Demuth’s task—which consists in paying tribute to his friend Williams through the poem—poses the problem of pictorial fixity and he manages to counterbalance it by his use of precisionist strategies derived from cubist practices. If the figure 5 corresponds to Barthes’s definition of punctum—a detail that touches the viewer—in the poem, Demuth’s painting recreates similar conditions as the figure 5 “rises from the scene, shoots out of it like an arrow, and pierces” the viewer (49). Based on Barthes’s study of intense immobility, this article will underline the common points between Williams’ imagist poem and Demuth’s precisionist painting so as to focus on the way they address the senses and promote a new understanding of temporality in art

A new connection of mRNP biogenesis and export with transcription-coupled repair

Although DNA repair is faster in the transcribed strand of active genes, little is known about the possible contribution of mRNP biogenesis and export in transcription-coupled repair (TCR). Interestingly, mutants of THO, a transcription complex involved in maintenance of genome integrity, mRNP biogenesis and export, were recently found to be deficient in nucleotide excision repair. In this study we show by molecular DNA repair analysis, that Sub2-Yra1 and Thp1-Sac3, two main mRNA export complexes, are required for efficient TCR in yeast. Careful analysis revealed that THO mutants are also specifically affected in TCR. Ribozyme-mediated mRNA self-cleavage between two hot spots for UV damage showed that efficient TCR does not depend on the nascent mRNA, neither in wild-type nor in mutant cells. Along with severe UV damage-dependent loss in processivity, RNAPII was found binding to chromatin upon UV irradiation in THO mutants, suggesting that RNAPII remains stalled at DNA lesions. Furthermore, Def1, a factor responsible for the degradation of stalled RNAPII, appears essential for the viability of THO mutants subjected to DNA damage. Our results indicate that RNAPII is not proficient for TCR in mRNP biogenesis and export mutants, opening new perspectives on our knowledge of TCR in eukaryotic cells

The Nup84 complex coordinates the DNA damage response to warrant genome integrity

DNA lesions interfere with cellular processes such as transcription and replication and need to be adequately resolved to warrant genome integrity. Beyond their primary role in molecule transport, nuclear pore complexes (NPCs) function in other processes such as transcription, nuclear organization and DNA double strand break (DSB) repair. Here we found that the removal of UV-induced DNA lesions by nucleotide excision repair (NER) is compromised in the absence of the Nup84 nuclear pore component. Importantly, nup84Δ cells show an exacerbated sensitivity to UV in early S phase and delayed replication fork progression, suggesting that unrepaired spontaneous DNA lesions persist during S phase. In addition, nup84Δ cells are defective in the repair of replication-born DSBs by sister chromatid recombination (SCR) and rely on post-replicative repair functions for normal proliferation, indicating dysfunctions in the cellular pathways that enable replication on damaged DNA templates. Altogether, our data reveal a central role of the NPC in the DNA damage response to facilitate replication progression through damaged DNA templates by promoting efficient NER and SCR and preventing chromosomal rearrangements.European Research Council ERC2014 AdG669898 TARLOOPMinisterio de Economía y Competitividad BFU2016-75058-PJunta de Andalucía PA12-BIO123

Manganese Stress Tolerance Depends on Yap1 and Stress-Activated MAP Kinases

Understanding which intracellular signaling pathways are activated by manganese stress is crucial to decipher how metal overload compromise cellular integrity. Here, we unveil a role for oxidative and cell wall stress signaling in the response to manganese stress in yeast. We find that the oxidative stress transcription factor Yap1 protects cells against manganese toxicity. Conversely, extracellular manganese addition causes a rapid decay in Yap1 protein levels. In addition, manganese stress activates the MAPKs Hog1 and Slt2 (Mpk1) and leads to an up-regulation of the Slt2 downstream transcription factor target Rlm1. Importantly, Yap1 and Slt2 are both required to protect cells from oxidative stress in mutants impaired in manganese detoxification. Under such circumstances, Slt2 activation is enhanced upon Yap1 depletion suggesting an interplay between different stress signaling nodes to optimize cellular stress responses and manganese tolerance.Universidad de Sevilla 2020/00001326Junta de Andalucía P20-RT-01220Ministerio de Ciencia e Innovación PID2019-105342GB-I0

IFN-gamma mediates the rejection of haematopoietic stem cells in IFN-gammaR1-deficient hosts.

International audienceBACKGROUND: Interferon-gamma receptor 1 (IFN-gammaR1) deficiency is a life-threatening inherited disorder, conferring predisposition to mycobacterial diseases. Haematopoietic stem cell transplantation (HSCT) is the only curative treatment available, but is hampered by a very high rate of graft rejection, even with intra-familial HLA-identical transplants. This high rejection rate is not seen in any other congenital disorders and remains unexplained. We studied the underlying mechanism in a mouse model of HSCT for IFN-gammaR1 deficiency. METHODS AND FINDINGS: We demonstrated that HSCT with cells from a syngenic C57BL/6 Ifngr1+/+ donor engrafted well and restored anti-mycobacterial immunity in naive, non-infected C57BL/6 Ifngr1-/- recipients. However, Ifngr1-/- mice previously infected with Mycobacterium bovis bacillus Calmette-Guérin (BCG) rejected HSCT. Like infected IFN-gammaR1-deficient humans, infected Ifngr1-/- mice displayed very high serum IFN-gamma levels before HSCT. The administration of a recombinant IFN-gamma-expressing AAV vector to Ifngr1-/- naive recipients also resulted in HSCT graft rejection. Transplantation was successful in Ifngr1-/- x Ifng-/- double-mutant mice, even after BCG infection. Finally, efficient antibody-mediated IFN-gamma depletion in infected Ifngr1-/- mice in vivo allowed subsequent engraftment. CONCLUSIONS: High serum IFN-gamma concentration is both necessary and sufficient for graft rejection in IFN-gammaR1-deficient mice, inhibiting the development of heterologous, IFN-gammaR1-expressing, haematopoietic cell lineages. These results confirm that IFN-gamma is an anti-haematopoietic cytokine in vivo. They also pave the way for HSCT management in IFN-gammaR1-deficient patients through IFN-gamma depletion from the blood. They further raise the possibility that depleting IFN-gamma may improve engraftment in other settings, such as HSCT from a haplo-identical or unrelated donor

Short-term telomere dynamics is associated with glucocorticoid levels in wild populations of roe deer

International audienceWhile evidence that telomere length is associated with health and mortality in humans and birds is accumulating, a large body of research is currently seeking to identify factors that modulate telomere dynamics. We tested the hypothesis that high levels of glucocorticoids in individuals under environmental stress should accelerate telomere shortening in two wild populations of roe deer (Capreolus capreolus) living in different ecological contexts. From two consecutive annual sampling sessions, we found that individuals with faster rates of telomere shortening had higher concentrations of fecal glucocorticoid metabolites, suggesting a functional link between glucocorticoid levels and telomere attrition rate. This relationship was consistent for both sexes and populations. This finding paves the way for further studies of the fitness consequences of exposure to environmental stressors in wild vertebrates

Review. Divergent selection for residual feed intake in the growing pig

To view supplementary material for this article, please visit https:/doi.org/10.1017/S175173111600286XThis review summarizes the results from the INRA (Institut National de la Recherche Agronomique) divergent selection experiment on residual feed intake (RFI) in growing Large White pigs during nine generations of selection. It discusses the remaining challenges and perspectives for the improvement of feed efficiency in growing pigs. The impacts on growing pigs raised under standard conditions and in alternative situations such as heat stress, inflammatory challenges or lactation have been studied. After nine generations of selection, the divergent selection for RFI led to highly significant ( P<0.001) line differences for RFI (−165 g/day in the low RFI (LRFI) line compared with high RFI line) and daily feed intake (−270 g/day). Low responses wereobserved on growth rate (−12.8 g/day, P <0.05) and body composition (+0.9mm backfat thickness, P = 0.57; −2.64% lean meat content, P<0.001) with a marked response on feed conversion ratio (−0.32 kg feed/kg gain, P<0.001). Reduced ultimate pH and increased lightness of the meat ( P<0.001) were observed in LRFI pigs with minor impact on the sensory quality of the meat. These changes in meat quality were associated with changes of the muscular energy metabolism. Reduced maintenance energy requirements (−10% after five generations of selection) and activity (−21% of time standing after six generations of selection) of LRFI pigs greatly contributed to the gain in energy efficiency. However, the impact of selection for RFI on the protein metabolism of the pig remains unclear. Digestibility of energy and nutrients was not affected by selection, neither for pigs fed conventional diets nor for pigs fed high-fibre diets. A significant improvement of digestive efficiency could likely be achieved by selecting pigs on fibre diets. No convincing genetic or blood biomarker has been identified for explaining the differences in RFI, suggesting that pigs have various ways to achieve an efficient use of feed. No deleterious impact of the selection on the sow reproduction performance was observed. The resource allocation theory states that low RFI may reduce the ability to cope with stressors,via the reduction of a buffer compartment dedicated to responses to stress. None of the experiments focussed on the response of pigs to stress or challenges could confirm this theory. Understanding the relationships between RFI and responses to stress and energy demanding processes, as such immunity and lactation, remains a major challenge for a better understanding of the underlying biological mechanisms of the trait and to reconcile the experimental results with the resource allocation theory