Reviews & Analysis

The crystal structure of the FERM-SH2 region of Tyk2 in complex with the cytoplasmic tail of an interferon-α receptor provides a first view of specific JAK-receptor recognition and reveals a central role of the heretofore-marginalized JAK SH2 domain in recognizing the cytokine-receptor box2 motif.

The crystal structure of the membrane insertase YidC reveals a hydrophilic groove in the cytoplasmic bilayer leaflet, suggesting a new mechanism of membrane-protein insertion.

A new report reveals how mammalian cells silence the DNA-damage response during mitosis to allow cell division to be completed in the presence of DNA lesions.

Genome-wide association studies have identified genes encoding major histocompatibility (MHC) class II molecules as the single most important predisposing factor for autoimmunity. A new study provides atomic insight into how the antigen receptors of intestinal T cells recognize dietary gluten that drives celiac disease pathogenesis when bound to the MHC class II molecule HLA-DQ2.5, the major genetic risk factor of celiac disease.

Structures of the deubiquitinating enzyme Rpn11 of the proteasomal 19S regulatory particle reveal its role in hydrolyzing the proximal ubiquitin from a protein that is about to be degraded.

Microhomology-mediated end joining (MMEJ) is a mechanism of DNA double-strand-break repair that creates deletions and promotes other types of genome instability. New in vivo and in vitro analyses demonstrate that the heterotrimeric replication protein A (RPA) complex prevents spontaneous annealing of microhomologies, thereby preventing genome-destabilizing MMEJ.

Housekeeping σ factors are initiation factors for the bacterial RNA polymerase at most promoters, whereas alternative σs direct focused responses to specific environmental conditions. Structural and functional analysis of an alternative σ complexed with its cognate −10 motif elucidates the mechanism for initiation of strand opening, highlighting two critical properties: why alternative σs, compared to housekeeping σs, recognize so few promoters and how their promoter-recognition strategy was diversified during evolution.

Ubiquitin E3 ligases catalyze the final step of the ubiquitination cascade, promoting the transfer of ubiquitin from the E2 to the substrate target. Recent structural and biochemical studies have given insights in the catalytic mechanisms of all three E3 ligase classes, as discussed in this Review.

Ubiquitin and ubiquitin-like (UBL) modifications occur primarily on lysine residues of target proteins to stimulate downstream signals. This Review discusses current knowledge of lysine specificity in ubiquitin and UBL targeting, with particular focus on the systems in which a detailed mechanism of modification and downstream signaling has been validated biochemically.

DNA metabolism is regulated by the ubiquitin and SUMO modifications, but DNA also influences whether and when these modifications occur. This Review describes the mutual interactions between DNA, ubiquitin and SUMO that occur in DNA-associated processes.

Whereas the proteasome degrades individual proteins modified with ubiquitin chains, autophagy degrades many proteins and organelles en masse. A pair of ubiquitin-like proteins (UBLs), Atg8 and Atg12, regulate autophagy-mediated degradation in a manner completely distinct from that of ubiquitin in the proteasome pathway, as discussed in this Review.

The endoplasmic reticulum–associated degradation (ERAD) pathway maintains protein homeostasis in the ER by retrotranslocating unwanted proteins to the cytosol for proteasomal degradation. This Review discusses the integral role of the ubiquitin system in ERAD, highlighting how the two pathways intertwine to facilitate transport across the ER membrane.

Long noncoding RNAs (lncRNAs) have divergent roles in the nuclei of higher eukaryotes, including chromatin modification and regulation of nuclear bodies. A new study adds a new lncRNA function to the current list: serving as a platform for trans-chromosomal associations. At least three gene loci located on different chromosomes are brought together around the transcription site of a lncRNA termed functional intergenic repeating RNA element (Firre).

Enhancers are cis-regulatory elements that enable precise spatiotemporal patterns of gene expression during development and are notable for their ability to function at large distances from their target genes. This Review discusses classic enhancer studies, placing these in the context of recent studies that confirm the role of enhancers in orchestrating gene expression during development and their significance in disease pathogenesis.

An ABC protein that binds the ribosomal exit site suggests a new mechanism for direct regulation of translation in response to changing ATP levels in the cell.

Hyperactivation of receptor tyrosine kinase pathways is a common theme in cancer. The recent demonstration that an imbalance between the fibroblast growth factor receptor 2–binding proteins Grb2 and phospholipase C-γ1 can lead to invasive behavior in the absence of growth factors highlights an emerging concept in cellular-signaling homeostasis.

Differences in the sex-chromosome karyotype of many animal species create imbalances between X-chromosome and autosomal gene products that require compensation. Genome-wide analyses have been instrumental in driving recent progress in understanding the transcriptional regulatory mechanisms underlying dosage compensation. This Review focuses on emerging models for dosage compensation in mammals, flies and nematodes.

The long-awaited crystal structure of Saccharomyces cerevisiae DNA polymerase ε reveals a unique domain never before observed in B-family DNA polymerases. This novel domain endows polymerase ε with a capacity for highly processive DNA synthesis.

The exosome complex has key roles in RNA processing and quality control. Single-particle EM analyses now provide compelling evidence for two distinct pathways by which substrate RNAs can pass through the exosome structure to reach the catalytic site for exonuclease digestion.

Enzymes that alter nucleosome structure or position are at the very center of gene and genome regulation, and understanding how, and to what extent, these diverse activities collaborate and control each other to shape the genome for dynamic regulation is a major challenge. A new study provides an important step in this direction by illustrating the cooperative nature of ATP-dependent chromatin-remodeling systems in mammalian cells.