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A study of drug-resistant lymphomas with hypermorphic mutations in PRC2 has identified a ‘methylation index’ by which cancer cells maintain optimal H3K27me3 levels for survival, emphasizing the importance of understanding how tumors adapt to changes in chromatin and to drug-resistance mutations.
The NADP+/NADPH coenzyme couple powers cellular biosynthesis and oxidative defense. A new study tracing glucose-derived deuterium during proline biosynthesis analyzes subcellular perturbations in NADPH utilization, revealing that NADP+/NADPH coenzyme pools in the cytosol and mitochondria are regulated independently.
Biased signaling gives hormones, probes or drugs distinct functional outcomes via the same receptor. The Biased Signaling Atlas (https://BiasedSignalingAtlas.org) provides a community hub with data and tools to advance this paradigm, which may yield safer and more potent drugs.
Profiling the resistance landscape to PRC2 inhibitors in EZH2-mutant lymphoma with CRISPR-suppressor scanning reveals drug addiction mutations and a repressive methylation ceiling. Surpassing the ceiling with SETD2 inhibition halts lymphoma growth.
An approach using glucose tracers and labeling of proline metabolites is applied to assess compartmentalized NADPH fluxes. The results show that NADPH fluxes in the cytosol and mitochondria are independently regulated, with no evidence of a shuttle.
Zhu et al. show how the growth-rate-dependent gene expression reshapes the landscape of cell-fate determination and highlight that expression capacities of genes have unbalanced response to growth variations.
Identifying new proteoforms — structural variants of proteins — is frequently challenging, particularly on the proteome-wide scale. A new study leverages their differential thermal stabilities to identify proteoform functional groups by deep thermal proteome profiling.
Applying thermal proteome profiling to acute B cell childhood leukemia cell lines combined with deep peptide fractionation and a graph-based clustering algorithm allows inference of functional proteoform groups and their association with drug response.
A new review article details how new structural insight regarding modular polyketide synthases (PKSs) helps us better understand the organization of catalytic events within a PKS module. The plausible models discussed will likely influence future PKS engineering efforts.
Engineering synthetic tools that facilitate decision-making in mammalian cells could enable myriad biomedical applications. Researchers have now developed a new system of inducer-controlled transcription factors to facilitate synthetic decision-making (LOGIC) in human cells based on modular protein-fusion cascades.
Live-cell HRMAS NMR spectroscopy and genome-scale metabolic modeling enable high-resolution analysis of dynamic, anaerobic metabolism in Clostridioides difficile, identifying the confluence of carbohydrate and amino acid fermentations for alanine synthesis.
Kim et al. used directed evolution methods to identify a high-fidelity SpCas9 variant, Sniper2L, which exhibits high general activity but maintains high specificity at a large number of target sites.
The authors show modular functionality of TetR-like proteins in mammalian cells, separating the protein–DNA and the protein–protein interaction. This allows for engineered ON- and OFF-type responses to stimuli, higher order and multi-input logics.
