Proximity proteome mapping reveals PD-L1-dependent pathways disrupted by anti-PD-L1 antibody specifically in EGFR-mutant lung cancer cells.

Background: PD-L1, a transmembrane ligand for immune checkpoint receptor PD1, has been successfully targeted to activate an anti-tumor immune response in a variety of solid tumors, including non-small cell lung cancer (NSCLC). Despite the success of targeting PD-L1, only about 20% of patients achieve a durable response. The reasons for the heterogeneity in response are not understood, although some molecular subtypes (e.

Consequences of aneuploidy in human fibroblasts with trisomy 21.

An extra copy of chromosome 21 causes Down syndrome, the most common genetic disease in humans. The mechanisms contributing to aneuploidy-related pathologies in this syndrome, independent of the identity of the triplicated genes, are not well defined. To characterize aneuploidy-driven phenotypes in trisomy 21 cells, we performed global transcriptome, proteome, and phenotypic analyses of primary human fibroblasts from individuals with Patau (trisomy 13), Edwards (trisomy 18), or Down syndromes.

Role of specialized composition of SWI/SNF complexes in prostate cancer lineage plasticity.

Advanced prostate cancer initially responds to hormonal treatment, but ultimately becomes resistant and requires more potent therapies. One mechanism of resistance observed in around 10-20% of these patients is lineage plasticity, which manifests in a partial or complete small cell or neuroendocrine prostate cancer (NEPC) phenotype. Here, we investigate the role of the mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complex in NEPC.

Dynamic Incorporation of Histone H3 Variants into Chromatin Is Essential for Acquisition of Aggressive Traits and Metastatic Colonization.

Metastasis is the leading cause of cancer mortality. Chromatin remodeling provides the foundation for the cellular reprogramming necessary to drive metastasis. However, little is known about the nature of this remodeling and its regulation.

KLF4 is involved in the organization and regulation of pluripotency-associated three-dimensional enhancer networks.

Cell fate transitions are accompanied by global transcriptional, epigenetic and topological changes driven by transcription factors, as is exemplified by reprogramming somatic cells to pluripotent stem cells through the expression of OCT4, KLF4, SOX2 and cMYC. How transcription factors orchestrate the complex molecular changes around their target gene loci remains incompletely understood. Here, using KLF4 as a paradigm, we provide a transcription-factor-centric view of chromatin reorganization and its association with three-dimensional enhancer rewiring and transcriptional changes during the reprogramming of mouse embryonic fibroblasts to pluripotent stem cells.

Robust, Reproducible, and Economical Phosphopeptide Enrichment Using Calcium Titanate.

Mass-spectrometry-based phosphoproteomics has revolutionized phosphoprotein analysis and enhanced our understanding of diverse and fundamental cellular processes important for human health and disease. Because of their relative scarcity, phosphopeptides must be enriched before analysis. Many different enrichment methods and materials have been described, and many reports have made claims about the advantages of particular materials and methodological variations.

Serine-Dependent Sphingolipid Synthesis Is a Metabolic Liability of Aneuploid Cells.

Aneuploidy disrupts cellular homeostasis. However, the molecular mechanisms underlying the physiological responses and adaptation to aneuploidy are not well understood. Deciphering these mechanisms is important because aneuploidy is associated with diseases, including intellectual disability and cancer.

The stress sigma factor of RNA polymerase RpoS/σ is a solvent-exposed open molecule in solution.

In bacteria, one primary and multiple alternative sigma (σ) factors associate with the RNA polymerase core enzyme (E) to form holoenzymes (Eσ) with different promoter recognition specificities. The alternative σ factor RpoS/σ is produced in stationary phase and under stress conditions and reprograms global gene expression to promote bacterial survival. To date, the three-dimensional structure of a full-length free σ factor remains elusive.

Post-transcriptional Regulation of De Novo Lipogenesis by mTORC1-S6K1-SRPK2 Signaling.

mTORC1 is a signal integrator and master regulator of cellular anabolic processes linked to cell growth and survival. Here, we demonstrate that mTORC1 promotes lipid biogenesis via SRPK2, a key regulator of RNA-binding SR proteins. mTORC1-activated S6K1 phosphorylates SRPK2 at Ser494, which primes Ser497 phosphorylation by CK1.

Recent advances in the characterization of Crl, the unconventional activator of the stress sigma factor σS/RpoS.

The bacterial RNA polymerase (RNAP) holoenzyme is a multisubunit core enzyme associated with a σ factor that is required for promoter-specific transcription initiation. Besides a primary σ responsible for most of the gene expression during active growth, bacteria contain alternative σ factors that control adaptive responses. A recurring strategy in the control of σ factor activity is their sequestration by anti-sigma factors that occlude the RNAP binding determinants, reducing their activity.

Binding interface between the Salmonella σ(S)/RpoS subunit of RNA polymerase and Crl: hints from bacterial species lacking crl.

In many Gram-negative bacteria, including Salmonella enterica serovar Typhimurium (S. Typhimurium), the sigma factor RpoS/σ(S) accumulates during stationary phase of growth, and associates with the core RNA polymerase enzyme (E) to promote transcription initiation of genes involved in general stress resistance and starvation survival. Whereas σ factors are usually inactivated upon interaction with anti-σ proteins, σ(S) binding to the Crl protein increases σ(S) activity by favouring its association to E.

(1)H, (13)C and (15)N resonance assignments of σ(S) activating protein Crl from Salmonella enterica serovar Typhimurium.

The general stress response in Enterobacteria, like Escherichia coli or Salmonella, is controlled by the transcription factor σ(S), encoded by the rpoS gene, which accumulates during stationary phase growth and associates with the core RNA polymerase enzyme (E) to promote transcription of genes involved in cell survival. Tight regulation of σ(S) is essential to preserve the balance between self-preservation under stress conditions and nutritional competence in the absence of stress. Whereas σ factors are generally inactivated upon interaction with anti-sigma proteins, σ(S) binding by the Crl protein facilitates the formation of the holoenzyme Eσ(S), and therefore σ(S)-controlled transcription.

Structural and functional features of Crl proteins and identification of conserved surface residues required for interaction with the RpoS/σS subunit of RNA polymerase.

In many γ-proteobacteria, the RpoS/σS sigma factor associates with the core RNAP (RNA polymerase) to modify global gene transcription in stationary phase and under stress conditions. The small regulatory protein Crl stimulates the association of σS with the core RNAP in Escherichia coli and Salmonella enterica serovar Typhimurium, through direct and specific interaction with σS. The structural determinants of Crl involved in σS binding are unknown.

Cross-talk between prion protein and quadruplex-forming nucleic acids: a dynamic complex formation.

Prion protein (PrP) is involved in lethal neurodegenerative diseases, and many issues remain unclear about its physio-pathological role. Quadruplex-forming nucleic acids (NAs) have been found to specifically bind to both PrP cellular and pathological isoforms. To clarify the relevance of these interactions, thermodynamic, kinetic and structural studies have been performed, using isothermal titration calorimetry, surface plasmon resonance and circular dichroism methodologies.

Natural phenylalanine hydroxylase variants that confer a mild phenotype affect the enzyme's conformational stability and oligomerization equilibrium.

Hyperphenylalaninemias are genetic diseases prevalently caused by mutations in the phenylalanine hydroxylase (PAH) gene. The wild-type PAH enzyme is a homotetramer regulated by its substrate, cofactor and phosphorylation. We reproduced a full-length wild-type protein and seven natural full-length PAH variants, p.