Biomedical subjects

Nathalie Carte

Publications and source records attributed to Nathalie Carte.

3 recordsLinked to original sources

PubMed2026

BRD9 Degraders Unleash GBAF Chromatin Remodeling Activity in Synovial Sarcoma.

UNLABELLED: Synovial sarcoma incorporates the SS18::SSX fusion oncoprotein into GLTSCR1-containing BRG1/BRM and associated factors (GBAF) complexes, which confers a dependency on the GBAF subunit BRD9. However, synovial sarcoma clinical trials with multiple BRD9 degraders failed to achieve clinically impactful remissions. In this study, we identified a mechanistic framework to explain these results. BRD9 depletion served to blunt proliferation in synovial sarcoma harboring minimal genomic alterations, rare in trial participants. In cultured cells, xenografts, and recombinant-purified complexes, BRD9 loss did not affect GBAF assembly. Although BRD9 degradation in synovial sarcoma reduced GBAF enrichment at target loci, BRD9-less complexes maintained or increased chromatin accessibility and associated gene transcription. Biochemical assays with purified recombinant GBAF demonstrated increased nucleosome sliding in the absence of BRD9. Together, these findings show that BRD9 restrains GBAF activity, with BRD9 degradation increasing enzymatic remodeling and target gene expression by fusion oncoprotein-distributed GBAFs in synovial sarcoma. This subtle epigenetic disturbance creates a low hurdle for synovial sarcoma to surpass, limiting the therapeutic efficacy of BRD9 degraders. SIGNIFICANCE: BRD9 represses the GBAF chromatin remodeling complex, which causes enhanced rather than disrupted SS18::SSX complex activity following BRD9 degradation and explains the lack of efficacy of pharmacological BRD9 degraders in synovial sarcoma.

Sarcoma, Synovial↗

PubMed2002

Glycosylation of human recombinant gonadotrophins: characterization and batch-to-batch consistency.

The glycan moiety of human recombinant gonadotrophins (r-hFSH, r-hLH, and r-hCG) produced in CHO cell lines has been characterized by a combination of chromatographic and mass spectrometric techniques, including both matrix-assisted laser desorption ionization and electrospray. Two glycan mapping methods have been developed for the three gonadotrophins that allow separation of the glycans according to either their charge or sialylation level or their antennarity. A method was also developed for r-hCG that permits the complete resolution of the N-glycan from the O-glycan species. Whereas the structure found for the N-glycans of the gonadotrophins was in agreement with the complex type model, the structure for an O-glycan of r-hCG, not yet described, has been unambiguously determined using nanoelectrospray ion trap mass spectrometry. Using these two glycan mapping methods, the high level of batch-to-batch consistency achieved for the glycosylation of the three recombinant gonadotrophins in commercial production has been shown. These data demonstrate the tight control that can be achieved in the manufacturing of complex recombinant therapeutic glycoproteins, which is a prerequisite to the delivering of a guaranteed dose of drug from vial to vial, and in turn to ensuring the clinical efficacy of the product.

Animals↗

PubMed2002

Comparative proteomics as a new tool for exploring human mitochondrial tRNA disorders.

More than 70 different point mutations in human mitochondrial tRNA genes are correlated with severe disorders, including fatal cardiopathies, encephalopathies, myopathies, and others. So far, investigation of the molecular impact(s) of mutations has focused on the affected tRNA itself by seeking structural and/or functional perturbations capable of interfering with synthesis of the 13 mitochondrion-encoded subunits of respiratory chain complexes. Here, a proteomic approach was used to investigate whether such mutations would affect the pattern of mitochondrial proteins at a broader level. Analysis of several hundred mitochondrial proteins from sibling cybrid cell lines by two-dimensional electrophoresis, an approach that takes into account all regulatory steps of mitochondrial and nuclear gene expression, indeed reveals a number of up- and downregulated proteins when healthy and single-point-mutation-carrying mitochondria representative of either MELAS or MERRF syndrome were compared. Assignment by mass spectrometry of the two proteins which exhibit obvious large quantitative decreases in the levels of both pathologic mitochondria identified nuclear-encoded subunits of cytochrome c oxidase, a respiratory chain complex. This clearly shows a linkage between the effects of mutations in mitochondrial tRNA genes and the steady-state level of nuclear-encoded proteins in mitochondria. It opens new routes toward a large-scale exploration of potential proteic partners involved in the genotype-phenotype correlation of mitochondrial disorders.

Amino Acid Sequence↗