News & Views in 2014

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.

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).

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.

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.

Every RNA polymerase II transcript receives a 5′-end 7-methylguanosine (m⁷G) cap, which is rapidly bound by the nuclear cap–binding complex (CBC). Two recent studies now reveal that the CBC associates with a variety of effector proteins that enable it to interrogate nascent RNA, discriminating between distinct RNA subclasses and routing them either toward distinct maturation pathways or toward decay. Thus, the CBC has an early role in policing cellular RNA.