Volume 31 Issue 5, May 2024

Since Nature Structural and Molecular Biology was started 30 years ago, our understanding of transcription and mRNA processing has been revolutionized through structural and mechanistic studies. Here, we present our personal views of the advances in understanding the production of mature eukaryotic mRNAs over the past decade.

Branch point selection is required for pre-mRNA splicing, and its mis-regulation is associated with many diseases. Two structural studies provide insights into the dynamics of active site formation and the spliceosomal proteins that may contribute to activation of the correct branch point in eukaryotic introns.

Spliceosome biogenesis and recycling remains a largely unexplored area. Two papers now reveal how protein chaperones remodel the 20S U5 snRNP, leading to formation of the U4/U6.U5 tri-snRNP.

ADP-ribosylation regulates the activity of numerous proteins involved in the DNA damage response and repair. A new study shows that telomeric DNA can be ADP-ribosylated by PARP1, and prompt removal of the ADP-ribose by TARG1 is essential to preserve telomere integrity, unveiling DNA–ADP-ribosylation as a novel player in telomere stability.

Stabilization of a branch structure would intuitively suggest a direct connection between trunk and bough, but in actin filament networks, cortactin clamps the branching Arp2/3 complex to the daughter filament. This has fundamental consequences for mechanistic understanding of actin branch turnover and cortactin biology.

Hexasomes are non-canonical nucleosomes that package DNA with six instead of eight histones. Here, the author contextualizes two recent studies on the interplay of the chromatin remodeler INO80 with hexasomes with historical literature on the subject.

The biogenesis and recycling of the ‘heart’ of the human spliceosome, the U5 small nuclear ribonucleoprotein (snRNP), requires CD2BP2 and TSSC4. Here the authors present cryo-electron microscopy structures that reveal how these protein chaperones orchestrate the ATP-independent (re)generation of the U5 snRNP.

Here the authors report the structure of the human 20S U5 snRNP, providing new insights into the assembly of the spliceosome building blocks.

The authors determined a cryo-EM structure of the pioneer factor NR5A2 bound to a nucleosome. NR5A2 releases nucleosomal DNA from histones by DNA minor anchor groove competition, providing a mechanism for pioneer factor activity during reprogramming

Here the authors structurally and functionally characterized a bacterial self-killing CBASS Cap5 immune defense system and demonstrated how it can be leveraged to limit bacterial infections.

The DNA polymerase α–primase complex undergoes dramatic configurational rearrangements to synthesize chimeric RNA-DNA primers across two separate active sites while maintaining simultaneous interactions at opposite ends of the primer–template duplex.

Telomeres are endogenous cellular targets of DNA ADP-ribosylation (DNA-ADPr). TARG1-regulated DNA-ADPr is coupled to lagging telomere DNA strand synthesis, and persistent DNA-ADPr, due to TARG1 deficiency, leads to telomere shortening and fragility.

Liu et al. show how cortactin stabilizes Arp2/3 actin branches by binding the daughter filament. It stabilizes the interface of activated Arp3 with the first actin subunit of the new filament, and its central repeats extend along successive daughter-filament subunits.

Rybak and Gagnon elucidate the mechanism of AUG codon avoidance by the minor isoleucine tRNA in Escherichia coli. The lysidinylated C34 in the anticodon loop of tRNA^Ile weakens interactions with the mRNA and destabilizes the EF-Tu ternary complex.

Precise protein synthesis is achieved by tRNA modifications. Here the authors revealed that modified cytidines in tRNA^Ile use their long side chains to make additional interactions with mRNA for stable tRNA binding on the ribosome.

Here, using mathematical modeling and an in vitro deadenylation system, the authors quantitatively demonstrate the effect of non-adenosines in the poly(A) tail and exemplify how tail sequence regulates mRNA stability.

Here, the authors structurally characterize two sequential complexes leading to prespliceosome assembly, providing insights into the mechanism of branch site proofreading in the human spliceosome.