Reviews & Analysis

James Kadonaga provides a retrospective of the biochemical analyses that demonstrated the role of chromatin in the regulation of RNA polymerase II transcription.

This personal Perspective by Joan and Ron Conaway describes the biochemical identification and characterization of three key transcription elongation factors, TFIIS, Elongin and ELL, and summarizes how the delineation of their functions has informed the understanding of the regulatory mechanisms that control elongation by RNA polymerase II.

This historical Perspective by John Lis summarizes the array of complementary biochemical, genetic, optical and genome-wide approaches that have enabled dissection of eukaryotic transcriptional mechanisms in their native, cellular environment, and considers the future insights offered by emerging technologies of ever-increasing sensitivity and resolution.

In this Review, Bob Roeder offers a personal, historical perspective of the landmark studies that elucidated the mechanism and regulation of eukaryotic transcription over five decades, from the initial discovery of three nuclear RNA polymerases to the structural, genomic and imaging approaches that continue to expand our understanding of the function of complex regulatory networks.

AAA ATPases constitute a large family of molecular chaperones, many of which unfold substrate proteins. Two recent cryo-EM studies of the AAA ATPase Cdc48 capture this enzyme in the midst of protein unfolding and reveal a universal substrate-threading mechanism for ring-shaped ATPases.

The ability of CRISPR-Cas9 to accurately and efficiently target and cleave any segment of double-stranded DNA based solely on the sequence of its loaded guide RNA has revolutionized genome editing. While many structural studies have shed light on the atomic details of DNA targeting, structures of the enzyme poised to perform catalysis have remained elusive. In this issue, Zhu, Clarke, Puppala et al. provide snapshots of the enzyme in action as it performs concerted cleavage of a target DNA¹.

The ‘tubulin code’, a set of post-translational modifications to the microtubule cytoskeleton that include removal of the C-terminal Tyr of α-tubulin, regulates the biological function of the polymer. Three studies now report structures of VASH1–SVBP and VASH2–SVBP heterodimers and provide insights into how these proteases recognize and cleave the terminal Tyr of α-tubulin.

Bryan Roth reviews how insights into the structures of G protein–coupled receptors that are targets of neuropsychiatric drugs contribute to understanding of their functions as well as to the discovery of new chemical tools and drugs.

Monoamine transporters (MATs) regulate neurotransmission via the reuptake of dopamine, serotonin and norepinephrine from the extra-neuronal space. This Review discusses recent advances in elucidating the structural dynamics and allosteric regulation of MATs.

Numerous proteins in dendrites and axons are synthesized locally. In this Review, the authors summarize current evidence for local mRNA translation in neurons and discuss the neuronal functions shown to be served by this process.

Abasic sites are among the most frequent DNA lesions, and when they occur within single-stranded DNA, their repair can give rise to genomic instability and mutations. One mechanism for the protection of abasic sites involves covalent attachment of 5-hydroxymethylcytosine-binding, embryonic stem cell–specific (HMCES) protein to DNA. Now, two research groups have elucidated the structural basis of the action of HMCES and its bacterial equivalent, YedK, revealing a unique and intriguing chemistry of DNA–protein crosslink formation.

New structural work sheds light on the architecture of otopetrin channels, offering insights into the mechanisms for proton permeation in this family.

Viral mRNA synthesis is an essential step in the influenza virus replication cycle and is a prime target for the development of new antivirals. New structures of the influenza virus RNA polymerase now unveil previously unknown details of influenza virus transcription.

Two recent cryo-EM structures of the human L-type heteromeric amino acid transporter LAT1–CD98hc reveal surprising new insights into both amino acid transport in the human body and the roles of CD98hc as a cell-surface antigen and trafficking chaperone.

Epigenetic memory of silent chromatin often requires robust feedback loops between factors processing small non-coding RNAs and enzymes involved in heterochromatin assembly. A study published in Molecular Cell now demonstrates that these feedback loops can persist in a phenotypically neutral state even when gene expression is reactivated, and that they maintain the potential to reinstall heterochromatin in later generations when conditions change.

Cytosine methylation (m⁵C) is one of the more disputed base modifications of the epitranscriptome, mostly because current methods for detection are prone to artifacts. A new approach to increase detection accuracy reveals intriguing evidence of a role for the tRNA methyltransferase NSUN2 in the methylation of mRNA.

A recent cryo-EM study has generated breakthrough insights into the molecular and structural bases of tau tangles from individuals who died of CTE.

In the ribosome-associated quality control (RQC) pathway, stalled ribosomes are ubiquitinated and dissociated into subunits. The nascent protein chain associated with the 60S ribosomal subunit is ubiquitinated by the E3 ligase Listerin (Ltn1) and is released from tRNA by ANKZF1 (Vms1) for proteasomal degradation. Shao and colleagues now report that ANKZF1 (Vms1)-cleaved tRNAs are recycled via a two-step process that requires the removal of a terminal 2′,3′-cyclic phosphate and the addition of CCA by TRNT1.

Ribonucleotides that are misincorporated into DNA during replication are removed by topoisomerase 1, which generates 3′-terminal adducts that are not amenable to DNA repair and thus compromise genome stability. A recent report by Li et al. reveals that Apn2/APE2 resolves such blocked 3′ termini, thereby suppressing topoisomerase 1–induced mutations at ribonucleotide monophosphate sites within the genome.

RNAs perform diverse cellular functions that are mediated at least in part by their structure. However, how RNA structure changes throughout the RNA lifecycle and how these changes affect RNA function remain incompletely understood. A detailed in vivo characterization of RNA structure in various cellular subcompartments now provides insights into how RNA structural changes influence translation, RNA decay, protein binding and RNA modification.