NRAS mRNA-Degrading Bifunctional Small Molecules Induce Diverse Cellular Morphological Changes in Cancer Cells

Therapeutic targeting of the oncogenic NRAS protein, which is constitutively activated in human cancers, with small molecules is a promising yet challenging anticancer strategy. Therefore, targeting the NRAS mRNA poses a feasible alternative that will likely yield new biological consequences due to the new mechanism of regulation at the post-transcriptional level. We report herein the first examples of a reversely regulating NRAS mRNA-degrading ribonuclease targeting chimeric small molecules (NRAS-RIBOTAC), which were assembled by conjugating a reported 4-aminoquinazoline G4-NRAS binder with a biphenyl RNase L binder. Among the obtained NRAS-RIBOTACs, 5 impacted G4-containing NRAS mRNA expression while it did not significantly impact the expression of NRAS protein in MD-MB-231 cells, which could be explained by the fact that the G4-containing NRAS transcript only accounts for a trace amount in comparison with the dominant G4-lacking NRAS mRNA. Furthermore, we report here for the first time the phenotypic evaluation of RIBOTACs in the unbiased phenotypic profiling method, cell painting assay. In comparison with the monovalent ribonuclease recruiter and G4-NRAS mRNA binder, selected RIBOTACs showed significant activities in inducing cellular morphological changes and demonstrated a new biological performance that is reflected by the diverse cellular morphological changes in cancer cells.

pubs.acs.org

Targeted degradation of USP7 in solid cancer cells reveals distinct effects of deubiquitinase degraders and inhibitors - Nature Communications

DUBs regulate key cellular processes, but selective tools are scarce. Here, the authors developed PROTACs for the DUB USP7, comparing degraders with inhibitors. The study provides a valuable toolbox f...

nature.com

Millions in funding for a new international study on cell division

mpi-dortmund.mpg.de

Ancient co-option of LTR retrotransposons as yeast centromeres - Nature

Evolutionarily related ‘proto-point’ centromeres providing resolution to the evolutionary origins of point centromeres are identified in yeast, and comparison shows they evolved in an ancestor with re...

nature.com

Podcast: Lise Meitner oder Die Spaltung der Welt

Als Wissenschaftlerin steht Lise Meitner auf einer Stufe mit Einstein, Heisenberg und Otto Hahn. Sie war 48-mal für den Nobelpreis nominiert. Ihre Geschichte erzählt vom Kampf gegen Diskriminierung, d...

ardaudiothek.de

M18BP1 valency and a distributed interaction footprint determine epigenetic centromere specification in humans - The EMBO Journal

The histone H3 variant CENP-A is considered an epigenetic landmark of centromeres. Its deposition reflects cell-cycle-regulated assembly of M18BP1, HJURP, and PLK1 on a divalent MIS18α/β scaffold. The...

link.springer.com

Monovalent pseudo-natural products supercharge degradation of IDO1 by its native E3 KLHDC3 - Nature Chemistry

In targeted protein degradation, a degrader molecule brings a neosubstrate protein proximal to a hijacked E3 ligase for its ubiquitination. Here, pseudo-natural products derived from (−)-myrtanol—iDeg...

nature.com

CUL4A-DDB1-DCAF10 is an N-recognin for N-terminally acetylated Src kinases - Nature Communications

Cells depend on early protein modifications for proper function. Here, the authors show that when Src-family signaling kinases lack their typical myristoylation, an alternative acetylated start is det...

nature.com

Design, Synthesis, and Structural Evolution of Pseudo‐Natural Product IDO1 Inhibitors and Degraders

The combination of bicyclic monoterpene- and pyrrolidine-alkaloid fragments yields novel pseudo-natural products. Biological characterization revealed that these iDegs are inhibitors and degraders of...

onlinelibrary.wiley.com

Dancing proteins keep cells moving

mpi-dortmund.mpg.de

Harnessing indole scaffolds to identify small-molecule IRE1α inhibitors modulating XBP1 mRNA splicing - Nature Communications

The dysregulation of the inositol-requiring enzyme 1 alpha (IRE1α) has been associated with multiple human diseases, so IRE1α-targeting small molecules present great therapeutic potential. Here, the authors report a series of substituted indoles as IRE1α inhibitors of good potency and selectivity, and show that the inhibitor IA107 allosterically inhibits IRE1α RNase activity via binding to the IRE1α kinase domain but without inhibiting the IRE1α dimerization.

nature.com

Myeloperoxidase transforms chromatin into neutrophil extracellular traps - Nature

Myeloperoxidase, a highly expressed neutrophil protein, disassembles nucleosomes, facilitating neutrophil extracellular trap (NET) formation, and binds stably to NETs extracellularly.

nature.com

Two routes, one goal – How the crown of cell division is manufactured

mpi-dortmund.mpg.de

The BUB1 and BUBR1 paralogs scaffold the kinetochore fibrous corona

The kinetochore fibrous corona docks on CENP-E and a second elusive receptor identified as the checkpoint protein BUB1.

science.org

Pushing calcium against the flow: high-speed pumps in the cell

mpi-dortmund.mpg.de

Molecular mechanism of ultrafast transport by plasma membrane Ca2+-ATPases - Nature

Structural insights into ultrafast Ca2+ transport by plasma membrane Ca2+-ATPases are provided, highlighting an essential role for PtdIns(4,5)P2 dynamics.

nature.com

MPI group leader appointed to University of Münster

mpi-dortmund.mpg.de

Molecular requirements for PLK1 activation by T-loop phosphorylation

Activation of PLK1, a master mitotic kinase, requires phosphorylation of its activation segment on Thr210, within a basic consensus sequence for Aurora kinases. Aurora B-dependent phosphorylation of T...

biorxiv.org

Packing DNA on time for cell division

mpi-dortmund.mpg.de