News & Views

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.

New structural analyses suggest two different models for poly(ADP-ribose) polymerase 1 (PARP1) activation by single- and double-strand DNA breaks, providing evidence for PARP1 activation in cis and in trans.

RNA silencing is a sequence-specific gene regulation system conserved in eukaryotes, at the core of which lies the Argonaute protein family. Crystallographic studies of eukaryotic Argonaute proteins now reveal remarkably similar overall structures to their prokaryotic homologs while shedding new light on the fundamental relationship between their conformational dynamics and sophisticated strategies to silence specific targets.

Finding biologically relevant targets is a prerequisite for understanding the function of any trans regulator of gene expression, but this can be particularly challenging with microRNAs (miRNAs). A study in this issue addresses the problem by identifying a novel mode of miRNA target recognition.

A complex of PUF (named after founding members Pumilio and Fem-3 binding factor) and Argonaute proteins can stall translation elongation on bound mRNAs by interacting with eEF1A and inhibiting its GTPase activity.

The Cbl family of RING finger ubiquitin ligases regulates signaling in many systems. Two new studies provide a structural basis for how phosphorylation of a specific tyrosine in the Cbl proteins enhances their ubiquitin ligase activity, giving insight into how ubiquitination by Cbl proteins is restricted to specific substrates.