Volume 30 Issue 9, September 2023

NuA4 is a highly conserved histone acetyltransferase complex that functions in transcription and DNA repair. Four groups have recently determined the structure of NuA4 from two different yeasts using cryo-EM, revealing important mechanistic details of its function and allowing a detailed comparison to the related SAGA complex.

New work shows that in mammals, the iDDR motif of telomere factor TRF2 inhibits the MRE11–RAD50–NBS1 (MRN) complex at chromosome ends through a direct iDDR–RAD50 interaction. Unrelated protein motifs in yeasts inhibit MRN functions via an analogous mechanism, suggesting a convergent evolution in eukaryotes to control MRN action at telomeres.

The microtubule motor dynein is regulated by lissencephaly-1 (Lis1) at several points during its complex activation process. Two papers reveal the molecular mechanism for two steps: the beginning, when Lis1 acts as a wedge to disrupt dynein’s autoinhibited conformation; and the end, when microtubule binding ejects Lis1 from the motor.

New cryo-electron microscopy (cryo-EM) structures of CDP- and CDP-choline-bound choline phosphotransferase 1 (CHPT1) and choline/ethanolamine phosphotransferase 1 (CEPT1), involved in the metabolism of the two main lipids in eukaryotic cell membranes, capture the membrane proteins at resolution <4 Å, sufficient to gain mechanistic insights into these enzymes.

Genome-scale CRISPR–Cas9 screens have identified genetic backgrounds that are vulnerable to inhibition of the SUMO modification pathway in human cells. These findings reveal that protein SUMOylation is essential for cell proliferation owing to a key role in complementary catenane resolution pathways that operate in interphase and mitosis to resolve intertwined DNA structures.

In vitro reconstitution of recognition of 80S ribosomes by CCR4–NOT, cryo-electron microscopy (cryoEM), crosslinking mass spectrometry and biochemical characterization reveal that CCR4–NOT specifically identifies ribosomes stalled during translation elongation. CCR4–NOT occupies the ribosomal exit site (E site) and locks the ribosomal L1 stalk in an open conformation to enforce the stalled state.

Using designed ankyrin repeat proteins (DARPins) technology, we discovered an α-helical conformation of the third variable (V3) loop on the human immunodeficiency virus 1 (HIV-1) envelope glycoprotein that renders the virus susceptible to broad neutralization at an intermediate entry stage after binding the CD4 receptor. Our results highlight the potential of post-attachment neutralization and enable exploitation of this helical region for inhibitor and vaccine design.

mRNAs that encode insulin in humans, mice, salmon and the fly Drosophila melanogaster are marked by methylated adenosines in the 3′ untranslated region (UTR). In D. melanogaster, these methylated adenosines are necessary for robust translation of the insulin mRNA into protein. In their absence, flies cannot regulate energy homeostasis and develop diabetes-like hallmarks.

Here, the authors demonstrate that the translation of the Drosophila transcript of insulin (dilp2) is regulated by methylation of N⁶-adenosine (m⁶A) in the 3′ UTR, at sites also conserved in mammals. In turn, this results in aberrant, diabetes-like functional phenotypes.

Inhibitor of apoptosis BIRC2 mediates cell death and survival. Tencer et al. report the molecular mechanism underlying BIRC2 cellular localization and describe the effect of BIRC2 inhibition on the death of cancer cells and HIV-1-infected T cells.

To study the dynamic 3D structure of specific loci, the authors combine a computer modeling scheme based on polymer physics with experimental validation. Their results indicate that chromatin dynamics are sufficiently fast to sample all possible locus conformations within minutes, generating wide dynamic variability within single cells.

Here the authors report how cohesin loader Scc2 is recruited to chromatin during replication by the processivity-promoting factor PCNA to support de novo cohesin loading onto replicated sister DNA and ensure sister chromatid cohesion.

In this study, Yang et al. show that the mitochondrial-stress-induced cleavage product of DELE1 oligomerizes to generate a signaling platform that activates a cascade of kinases, triggering the integrated stress response.

Hertz et al. use CRISPR screening to identify genetic vulnerabilities to inhibition of SUMOylation in human cells. They show that SUMO exerts its essential role in cell proliferation via NIP45- and BTRR-PICH-mediated DNA catenane resolution pathways.

Using cryo-EM, the authors show that the mammalian CCR4–NOT complex specifically recognizes stalled translating ribosomes similar to the yeast complex, locks them in a translation-incompetent state and coordinates their ubiquitylation, highlighting its central role in linking translation to mRNA stability.

The third variable (V3) loop on the HIV-1 Env glycoprotein is required for viral entry. Here, the authors applied DARPin technology to produce broadly neutralizing inhibitors targeting a region of V3 that becomes accessible after binding to the CD4 receptor.

Here, the authors use cryo-EM, biochemical and yeast assays of the HAT NuA4–Tip60 to reveal its mechanism of acetylating distant nucleosomes through the Epl1 linker establishing long-range chromatin interactions.

Here, the authors show that DNA-PK and TRF2, via its iDDR, suppress MRN nucleolytic processing of leading-end blunt telomeres, which are instead processed by Apollo or, in its absence, are aberrantly fused by alternative end-joining.

Using cryo-EM, Karasmanis, Reimer, and Kendrick et al. reveal a Lis1-mediated dynein dimer, termed Chi, that serves as intermediate state in relieving dynein’s autoinhibition.

LIS1 is a critical activator of dynein-mediated retrograde transport. Ton et al. reveal that microtubule binding by dynein initiates a cascade of structural changes that trigger LIS1 dissociation from dynein prior to transport, providing insights into dynein activation.

Here the authors present the high-resolution structures of 17 antibiotics bound to Escherichia coli ribosomes, which may inform the development of new antibacterial agents. Their results unveil a conserved manner of antibiotic binding to the ribosome, including ordered water molecules.

Here the authors develop a single-cell multiomics sequencing method (scCARE-seq), which allows the simultaneous probing of 3D chromatin architecture and transcription for single cells. Using scCARE-seq they explore the relationship between the 3D genome and transcriptome in cell fate transitions and the cell cycle.