Biology subjects

Aube, F.

Publications and source records attributed to Aube, F..

5 recordsLinked to original sources

bioRxiv2023

Metabolism-dependent secondary effect of anti-MAPK cancer therapy on DNA repair

Amino acid bioavailability impacts mRNA translation in a codon depending manner. Here, we report that the anti-cancer MAPK inhibitors (MAPKi) decrease the intracellular concentration of aspartate and glutamate in melanoma cells. This results in the accumulation of ribosomes on codons corresponding to these amino acids and triggers the translation-dependent degradation of mRNAs encoding aspartate- and glutamate-rich proteins mostly involved in DNA metabolism. Consequently, cells that survive to MAPKi degrade aspartate and glutamate to generate energy, which simultaneously decreases their needs in amino acids owing to the downregulation of aspartate- and glutamate-rich proteins involved in cell proliferation. Concomitantly, the downregulation of aspartate- and glutamate-rich proteins involved in DNA repair increases DNA damage loads. Thus, DNA repair defects, and therefore mutations, are, at least in part, a secondary effect of the metabolic adaptation of cells exposed to MAPKi.

cancer biology↗

bioRxiv2020

Translation-dependent and independent mRNA decay occur through mutually exclusive pathways that are defined by ribosome density during T Cell activation.

mRNA translation and degradation are strongly interconnected processes that participate in the fine tuning of gene expression. Particularly, targeting mRNAs to translation-dependent degradation (TDD) could attenuate protein expression by making any increase in mRNA translation self-limiting. However, the extent to which TDD is a general mechanism for limiting protein expression is currently unknown. Here we describe a comprehensive analysis of basal and signal-induced TDD in mouse primary CD4 T cells. Our data indicate that most cellular transcripts are decayed to some extent in a translation-dependent manner, both in resting and activated cells. Our analysis further identifies the length of untranslated regions, the density of ribosomes and the GC content of the coding region as major determinants of TDD magnitude. Consistent with this, all transcripts that undergo changes in ribosome density upon T cell activation display a corresponding change in their TDD level. Surprisingly, the amplitude of translation-independent mRNA decay (TID) appears as a mirror image of TDD. Moreover, TID also responds to changes in ribosome density upon T cell activation but in the opposite direction from the one observed for TDD. Our data demonstrate a strong interconnection between mRNA translation and decay in mammalian cells. Furthermore, they indicate that ribosome density is a major determinant of the pathway by which transcripts are degraded within cells.

genomics↗

bioRxiv2019

Interplay between gene nucleotide composition bias and splicing

To characterize the rules governing exon recognition during splicing, we analysed dozens of RNA-seq datasets and identified ~3,200 GC-rich exons and ~4,000 AT-rich exons whose inclusion depends on different sets of splicing factors. We show that GC-rich exons have predicted RNA secondary structures at 5-ss, and are dependent on U1 snRNP-associated proteins. In contrast, AT-rich exons have a large number of branchpoints and SF1-or U2AF2-binding sites and are dependent on U2 snRNP-associated proteins. Nucleotide composition bias also influences local chromatin organization, with consequences for exon recognition during splicing. As the GC content of exons correlates with that of their hosting genes, isochores and topologically-associated domains, we propose that regional nucleotide composition bias leaves a local footprint at the exon level and induces constraints during splicing that can be alleviated by local chromatin organization and recruitment of specific splicing factors. Therefore, nucleotide composition bias establishes a direct link between genome organization and local regulatory processes, like alternative splicing.

molecular biology↗

bioRxiv2018

Interplay between coding and exonic splicing regulatory sequences

The inclusion of exons during the splicing process depends on the binding of splicing factors to short low-complexity regulatory sequences. The relationship between exonic splicing regulatory sequences and coding sequences is still poorly understood. We demonstrate that exons that are coregulated by any splicing factor share a similar nucleotide composition bias. We next demonstrate that coregulated exons preferentially code for amino acids with similar physicochemical properties because of the non-randomness properties of the genetic code. Indeed, amino acids sharing physicochemical properties correspond to codons that have the same nucleotide composition bias. These observations reveal an unanticipated bidirectional interplay between the physicochemical features encoded by exons and exon splicing regulation by splicing factors. We propose that the splicing regulation of an exon by a splicing factor is tightly interconnected with the physicochemical properties of the exon-encoded protein domain depending on the splicing-factor affinity for specific nucleotides.

genomics↗

bioRxiv2017

Efficient genome editing in primary cells and in vivo using viral-derived "Nanoblades" loaded with Cas9/sgRNA ribonucleoproteins

Programmable nucleases have enabled rapid and accessible genome engineering in eukaryotic cells and living organisms. However, their delivery into target cells can be technically challenging when working with primary cells or in vivo. Using engineered murine leukemia virus-like particles loaded with Cas9/sgRNA ribonucleoproteins (\"Nanoblades\"), we were able to induce efficient genome-editing in cell lines and primary cells including human induced pluripotent stem cells, human hematopoietic stem cells and mouse bone-marrow cells. Transgene-free Nanoblades were also capable of in vivo genome-editing in mouse embryos and in the liver of injected mice. Nanoblades can be complexed with donor DNA for \"all-in-one\" homology-directed repair or programmed with modified Cas9 variants to mediate transcriptional up-regulation of target genes. Nanoblades preparation process is simple, relatively inexpensive and can be easily implemented in any laboratory equipped for cellular biology.

cell biology↗