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A single-molecule approach using magnetic tweezers shows that DNA strand separation alone can trigger a lock at TusTer sites where oppositely moving replisomes on circular bacterial chromosomes must avoid crashing. The results support a 'mousetrap' model in which replication-related proteins are not necessary and strand separation is followed by an interaction between Tus and C6 of the Ter site that sets up a hierarchy of interactions to allow the TusTer complex to progressively strengthen. Cover art by Erin Dewalt, based on an image provided by TU Delft/Tremani. Article, p579; News & Views, p550
Chemical probes are proven tools for biological research and early-stage drug development, but how can chemical biologists make them more useful to the broader scientific community?
Chemical probes are powerful reagents with increasing impacts on biomedical research. However, probes of poor quality or that are used incorrectly generate misleading results. To help address these shortcomings, we will create a community-driven wiki resource to improve quality and convey current best practice.
Epigenetic chemical probes are having a strong impact in biological discovery and target validation. Systematic coverage of emerging epigenetic target classes with these potent, selective, cell-active chemical tools will profoundly influence understanding of the human biology and pathology of chromatin-templated mechanisms.
A powerful, high-throughput single-molecule approach to probe the nanoscale mechanical properties of the Tus–Ter protein–DNA complex reveals that the Tus–Ter-induced lock in unzipping at the nonpermissive face requires only DNA strand separation and involves a progressive strengthening of the Tus–Ter complex.
Many peptide-based natural products require a leader peptide to reach their final modified form, but the identification of general rules for leader peptide interactions have been stymied by the diversity of these molecules. Two papers reporting crystallographic and bioinformatic analysis of these systems now reveal a structurally conserved domain that mediates leader peptide binding.
A small molecule targeting the protein-protein interaction between a chromatin binding protein and an oncogenic transcription factor shows therapeutic potential in a subtype of acute myeloid leukemia.
5-Formylcytosine (5fC), produced by TET-mediated oxidation of 5-methylcytosine, is considered an intermediate in active DNA demethylation. Labeling studies and LC/MS analysis across mouse developmental stages reveals that 5fC modifications are more persistent in the genome and may have other functional roles.
Structural and biochemical analysis of the heterocyclase that acts on a ribosomally synthesized and post-translationally modified peptide identifies the basis for leader peptide activation and facilitates engineering of a constitutively active enzyme.
Bioinformatic and biochemical analyses define a conserved domain present in the biosynthetic clusters for ribosomally synthesized and post-translationally modified peptides (RiPPs) that recognizes the leader peptide and thus controls downstream processing.
The p30 isoform of C/EBPα associated with leukemia interacts with WDR5, a component of the SET/MLL histone methyltransferase complex. A small molecule, OICR-9429, disrupted p30-WDR5 interactions, resulting in differentiation of p30-expressing leukemia cells.
Tus protein bound to Ter sites on circular bacterial chromosomes provides a way to avoid random crashes of opposing replication forks. DNA-unzipping experiments show that the Tus–Ter–induced lock during unzipping at the nonpermissive face requires only DNA-strand separation.
Structural, spectroscopic and kinetic analyses suggest that class II benzoyl-CoA reductases from anaerobic bacteria use an unusual tungsten cofactor and a conserved histidine to perform a reduction akin to the widely used Birch reduction in organic chemistry.
Pseudouridine (ψ) is a C-linked uracil modification originally discovered in tRNA. MS analysis and CeU-Seq, a method that permits chemical tagging, pulldown and sequencing of ψ residues, reveal that these modifications are more abundant in the mammalian transcriptome than previously thought.
Carotenoid biosynthesis requires isomerization of the central double bond. Informatic, spectroscopic and functional characterization of Z-ISO, a protein involved in the process, demonstrates that it is a standalone enzyme with unusual heme-dependent chemistry.
A bioinformatics pipeline guided by genomic hints of where to look led to the identification and validation of several new classes of self-cleaving ribozymes and several catalytic RNA motifs related to the known hammerhead or HDV ribozymes.
The use of a high-affinity VHL ligand allows the development of chimeric molecules that promote the association of ERRα or RIPK2 with the VHL E3 ubiquitin ligase complex, resulting in protein degradation.