Volume 29 Issue 8, August 2022

CST is both an ssDNA-binding complex and a DNA Pol-α/primase cofactor that coordinates the switch from G-strand elongation to C-strand fill-in during telomere maintenance. Four papers in Nature Structural & Molecular Biology and Nature provide transformative insights into CST activity, providing a platform to understand lagging-strand synthesis genome wide.

A study published in Nature Structural & Molecular Biology now unveils, at the atomic level, the initial mechanisms of prion toxicity, providing insights into the pathogenic mechanisms of a protein neurodegenerative disease caused by protein misfolding.

Amplification of oncogene expression through extrachromosomal DNA is a common feature of many cancers and is associated with poor outcomes. Hung et al. review how regulation of extrachromosomal DNA gene expression is linked to alterations in chromatin structure and changes in contacts with DNA regulatory elements.

Here, the authors find that histone demethylase Epe1-mediated stress resistance is regulated by proteasome-dependent truncation, allowing heterochromatin to reprogram gene expression that confers antifungal resistance to some fission yeast cells in the population.

This work reveals the structural and biochemical basis for phosphorylation-dependent day/night signaling by KaiC in the cyanobacterial circadian clock.

Cryo-EM, X-ray crystallography and crosslinking mass spectrometry are harnessed to solve the structure of the full-length Rho-GEF P-Rex1, uncovering a two-layered mechanism of autoinhibition released upon Gβγ and PI(3,4,5)P3 binding.

Functional assays and cryo-EM structures show that ubiquitin binding and a cofactor drive protein quality-control client selection by the hybrid E2/E3 enzyme UBE2O.

Foutel et. al. identify conformational buffering as a mechanism for functional selection in intrinsically disordered protein regions that allows robust encoding of a tethering function by a hypervariable disordered linker through compensatory changes in sequence length and composition.

An endogenous proteasome inhibitor was identified 30 years ago, but its mechanism remained unclear. Rawson et al. show that this inhibitor is present within the interior of the proteasome, where it simultaneously inhibits all six active sites.

Elango et al. identify a new class of substrates on which the Fanconi anemia SLX4–XPF nuclease operates to mediate homologous recombination at DNA–protein replication fork barriers and promote cellular tolerance of DNA–protein cross-links.

Cryo-EM analysis of the human CST–Polα/primase complex reveals a metazoan-specific mode of interaction between CST and DNA polymerase α that is proposed to function in telomeric recruitment of Polα/primase for C-strand maintenance.

Clemons and colleagues identify a guided entry of tail-anchored proteins (GET) pathway in the pathogen Giardia intestinalis and characterize it structurally, revealing several previously unknown structures of the central protein Get3. The work resolves some important open questions and results in a comprehensive model for the insertion of tail-anchored membrane proteins.

The H-latch is a well-defined structural change occurring in PrP^C bound to the neurotoxic antibody POM1, and its presence shows a positive correlation with neurotoxicity. Inhibition of the H-latch prolongs the lifespan of prion-diseased mice.