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Many fusion oncoproteins (FOs) form condensates, some form in the nucleus and regulate gene expression while others form in the cytoplasm and promote cell signaling. In this work, the authors report the analysis of physicochemical features to enable prediction of FO condensation behavior.

Arabzade, Shirnekhi, Varadharajan, Ippagunta and colleagues show that the zinc finger translocation-associated (ZFTA) fusion oncoproteins gain intrinsically disordered regions, inducing nuclear condensate formation and oncogenic activation.

Tumor suppressor p53 can activate BAX or BAK; this activity is opposed by antiapoptotic protein BCL-xL, which sequesters p53. Now Kriwacki, Green and colleagues characterize the human p53–BCL-xL complex by NMR spectroscopy, thus allowing mutagenesis analyses to dissect p53's nuclear and cytosolic functions and BCL-xL's antiapoptotic mechanisms.

p14ARF drives NPM1 phase separation and forms meso-scale assemblies that limit NPM1 dynamics. Here the authors show that p14ARF hydrophobic residues enhance NPM1 phase separation, promote p14ARF nucleolar partitioning, nucleolar NPM1 immobilization, and reduce cell viability.

The cyclin-dependent kinase (Cdk) inhibitor p27^Kip1 (p27) folds upon binding to Cdk/cyclin complexes and during cell cycle progression p27 becomes phosphorylated, which triggers its ubiquitination and degradation. Here the authors use an integrated approach and show that Cdk2/cyclin A-bound p27 samples lowly-populated conformations that dynamically anticipate the sequential steps of the signaling cascade.

The dynamic interplay between p53 and Mdm2 triggers cell cycle arrest after DNA damage. A new study reveals that disorder in the transactivation domain of p53 is important for tuning this negative feedback system to ensure normal cellular signaling responses.

Here, the authors use small angle neutron scattering and coarse-grained molecular dynamics simulations to demonstrate that condensates based on the granular components of nucleoli are network fluids.

Whole-genome sequencing of medulloblastoma samples reveals several recurrent mutations in genes not previously implicated in the disease, many of which affect components of the epigenetic machinery in different disease subgroups.

Membraneless cellular assemblies termed biomolecular condensates — into which diverse biopolymers partition — mediate myriad biological processes. A study now reveals that physicochemical features, not specific stereochemistry, influence whether small molecules are enriched within or excluded from a diverse panel of condensates.

Heterotypic multicomponent interactions are shown to dominate the liquid–liquid phase separation that enables the formation of intracellular condensates.

Comprehensive genomic and transcriptomics analyses of more than 1,300 cases of childhood T-lineage acute lymphoblastic leukaemia identify 15 distinct subtypes that are associated with specific outcomes.

Proteins involved in epigenetic regulation are frequently mutated in several paediatric cancers. Here, Huether et al.characterize the somatic mutation frequency across 21 paediatric cancer subtypes by sequencing 633 epigenetic genes in over 1,000 tumours; generating a rich data set for investigating epigenetic dysregulation.

The nucleolus is a membrane-less organelle formed through liquid–liquid phase separation (LLPS). Here the authors use biophysical methods and show that the nucleolar protein nucleophosmin (NPM1) also undergoes LLPS through homotypic, inter-NPM1 interactions and discuss implications for the ribosome biogenesis process.

The nucleolus is a membrane-less organelle and both Nucleophosmin (NPM1) and Surfeit locus protein 6 (SURF6) are abundant proteins within the nucleolus. Here the authors employ biophysical methods to study the properties of NPM1-S6N droplets and provide insights into the role of SURF6 in maintaining and modulating the liquid-like structure of the nucleolus.

Post-translational modification of residues in an intrinsically disordered region of Bcl-XL promotes interactions with its folded core and allosterically reduces affinity for proapoptotic BH3-domain-containing proteins, resulting in apoptosis.

NMR reveals the dynamic stretching ability of the subdomain LH of the intrinsically disordered p21, providing a physical basis for the binding and functional diversity in its cell cycle regulatory role as a modulator of Cdk–cyclin complexes.

π-stacking interactions unique between residues of PUMA and Bcl-xL, which lead to the unfolding of Bcl-xL via an allosteric mechanism, are required to disrupt p53–Bcl-xL interaction and induce apoptosis. This is the first example of regulated protein unfolding for signal transmission.

RING E3 ligases mediate transfer of ubiquitin-like proteins from an E2 ligase to a substrate, but how this occurs is a long-standing mystery. Docking E2-RING structures onto a new crystal structure of the C-terminal domain of the E3-RING CUL1 in complex with the RBX1 RING protein now shows how a conformational change in RBX1 allows for the transfer by closing a gap between CUL1 and the E2.

Genomic analysis of 491 medulloblastoma samples, including methylation profiling of 1,256 cases, effectively assigns candidate drivers to most tumours across all molecular subgroups.

Vignali and colleagues show that the inhibitory receptor LAG3 interferes with TCR signaling and T cell activation by lowering the pH at the immune synapse, which causes the dissociation of the tyrosine kinase Lck from the CD4 or CD8 co-receptor.

This work shows that treatments used for acute myeloid leukaemia and targeted therapies could be used for early T-cell precursor acute lymphoblastic leukaemia.

Anna Andersson, Tanja Gruber, James Downing and colleagues report a genomic analysis of infant acute lymphoblastic leukemias with MLL rearrangements. They identify recurrent activating mutations in tyrosine kinase, phosphatidylinositol 3-kinase and RAS pathway genes but find that these mutations were often present in minor subclones and lost at the time of relapse.

APC/C is an E3 ligase complex of ~1.5 MDa that regulates cell division. APC/C^CDH1 is inhibited during interphase by EMI1. Now, NMR spectroscopy, electron microscopy and enzymology analyses are integrated, revealing that EMI1's 143-residue C-terminal domain binds distinct regions of APC/C^CDH1 to block the substrate-binding site and inhibit ubiquitin-chain elongation.

When the proapoptotic effector proteins BAX and BAK bind the BH3 domain of BID or BIM, they undergo conformational changes and oligomerization followed by insertion into the mitochondrial outer membranes, which leads to their permeabilization and, eventually, apoptosis. The NMR structure of the human BID BH3–BAK complex now provides structural insight into BAK activation.

ABCC4 is a chemotherapeutic drug exporter highly expressed in acute myeloid leukemia. Here, the authors demonstrate that MPP1 anchors ABCC4 to the outer cell membrane mediating drug resistance in leukemic cells and identify antimycin A as a chemical probe that disrupts such interaction and restores sensitivity.

David Ellison and colleagues report whole-genome sequencing of pediatric low-grade gliomas, the most common pediatric brain tumor. They identify a range of genomic alterations, including recurrent and mutually exclusive duplications of the FGFR1 region encoding the tyrosine kinase domain and rearrangements of MYB.

Suzanne Baker, Jinghui Zhang and colleagues report the identification of recurrent somatic mutations in the bone morphogenetic protein (BMP) receptor ACVR1 in 32% of diffuse intrinsic pontine gliomas.