Reviews & Analysis

Exon junction complexes (EJCs) are deposited on mRNAs during splicing and are key regulators of the post-transcriptional fate of messenger ribonucleoprotein particles (mRNPs). Two recent papers reporting on the transcriptome-wide mapping of EJC-binding sites in human cells reveal an unexpected heterogeneity of EJC distribution on mRNAs and a tight network of EJC–SR protein interactions contributing to the formation of a higher-order, compacted mRNP structure.

A newly uncovered activity of a family of Polycomb-group proteins provides insight into the mechanisms by which active genes become repressed during the transition from pluripotency to restricted cell fates as stem cells undergo lineage specification.

Three structures were recently reported for tyrosyl DNA phosphodiesterase 2 (Tdp2), a protein that protects the metazoan genome from shredding following abortive topoisomerase activity. The physiological significance of these findings is discussed here.

Histone post-translational modifications (PTMs) can directly influence histone-DNA and histone-histone interactions, or they can be targeted by protein effectors, or histone readers. This Review outlines known readers of histone PTMs, details their mechanism of action and the functional significance of histone PTM recognition and discusses cross-talk between protein effectors and consequences of the combinatorial readout of PTMs.

Two recent reports on the structures of cobalamin riboswitches uncover amazing details on how a ubiquitous riboswitch class selectively grips a large and ancient coenzyme, revealing that some variants in this class have evolved to detect a different metabolite target.

Mitotic exit follows shortly after microtubule attachment of the last unattached kinetochore. Two new studies illustrate the molecular basis of this dependency.

According to the 'classical' view, histone modifications are established in an identical fashion on both copies of each of the four core histones, resulting in 'symmetrically' modified nucleosomes. Now, a new study challenges this notion by demonstrating that asymmetric histone modifications exist on individual mononucleosomes in native chromatin and that symmetric and asymmetric modifications signal different biological outcomes, suggesting a radically expanded histone code.

TET and JBP proteins catalyze the oxidation of methylated C bases in the mammalian genome and of the methyl group of T bases in kinetoplastid genomes, respectively. A recent study in Nature Structural & Molecular Biology suggests a new function of 5-methylcytosine oxidation in regulating RNA polymerase II elongation rate that is reminiscent of that of base J in transcription termination in Leishmania.

The number and types of known functional noncoding RNAs (ncRNAs) has increased considerably over the past few years, and both cis- and trans-acting ncRNAs have been reported. This Review focuses on long- and short-sized ncRNAs that act in cis; that is, where both the regulatory RNA and the target gene are transcribed from the same locus.

Endoplasmic reticulum–associated degradation (ERAD) is a cellular protein quality-control process that disposes of proteasomal substrates from the early secretory pathway. Recent work shows that the endoplasmic reticulum–resident rhomboid protease RHBDL4 facilitates ERAD by recognizing and cleaving integral membrane substrates. The work indicates that intramembrane proteolysis may have a general role in the extraction of misfolded membrane proteins from the endoplasmic reticulum.

Maintenance of genome integrity, cell division and gene expression have all been shown to be regulated by the condensation of DNA into heterochromatin. In a study published in this issue, Bulut-Karslioglu et al. reveal a new heterochromatin function for transcription factors in a mammalian system. They show that instead of activating gene expression, in the context of heterochromatic repeats, specific transcription factors are necessary for the maintenance of transcriptional repression and heterochromatin.

The recently solved crystal structure of the procollagen C propeptide reveals the basis for chain selectivity as well as an unexpected asymmetry to this homotrimeric molecule. In addition, mapping disease-causing mutations to the structure demonstrates clear correlation between severity of disease and mutation location.

SecY and Sec61 translocons mediate the orderly insertion of transmembrane segments into the lipid bilayer during membrane-protein biogenesis. Reporting in this issue, Ismail et al. now use a SecM-based molecular force sensor to show that the translocon exerts a pulling force on the nascent chain that is capable of mechanical action at two distinct stages of the insertion process.

A number of events must occur to preserve the integrity of the chromatin template during gene transcription. A study in this issue reveals a novel mechanism whereby chromatin remodelers are recruited to histone modifications within gene bodies to prevent aberrant histone exchange during transcriptional elongation.

Eukaryotic ribosomal subunits are assembled in the nucleus and exported in a functionally inactive state to the cytoplasm, where they undergo final maturation steps before initiating translation. In the case of pre-40S subunits, these steps involve cleavage of the 20S pre-rRNA to the mature 18S rRNA. Two recent studies have surprisingly revealed that mature 60S subunits, aided by the translation initiation factor eIF5b (known as Fun12 in yeast), bind pre-40S subunits to assess their translation 'potential' before triggering cleavage of 20S pre-rRNA.

One of the surprising discoveries in the genomic age was the presence in plant genomes of two noncanonical DNA-dependent RNA polymerases involved in small RNA–mediated gene silencing. Two recent studies map the binding sites of RNA polymerase V, uncovering new mysteries concerning the targeting and function of this enigmatic enzyme.

The application of time-resolved NMR spectroscopy to histone phosphorylation dynamics reveals mechanistic hierarchies within the active sites of the enzymes that regulate chromatin, thereby shedding new light on the complexity of the histone code.

The search for the holy replicator has been revitalized through ultradeep sequencing of small RNA–primed single-stranded DNA. Saturation sequencing provides an explanation for the lack of overlap in prior data sets, suggests that frequency of origin usage but not site selection is developmentally regulated, and uncovers a complex four-stranded DNA structure associated with most origins.

The recent mapping and modeling of protein-protein interfaces between general transcription factors TFIIE, TFIIH and Pol II have provided new insights into TFIIH-mediated melting of the transcription start site to form an open Pol II preinitiation complex and the stabilization of the complex by TFIIE, leading to a new mechanistic model for open-complex formation.

HIV-1 avoids the immune detection of infected cells by preventing class I molecules of the major histocompatibility complex (MHC-I) bound to viral peptides from reaching the cell surface. A new structure shows how Nef turns MHC-I from a noncargo into a cargo for the clathrin adaptor AP-1, thus directing MHC-I to the lysosome instead of the plasma membrane.