Volume 21 Issue 3, March 2014

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.

Rpn11, the only essential deubiquitinase (DUB) of the 26S proteasome, sits at the top of the substrate entry pathway and facilitates substrate degradation through cotranslocational deubiquitination. The structure of the Rpn11–Rpn8 complex, together with functional assays, offers insight into Rpn11's promiscuous DUB activity during proteasomal degradation.

Secretory proteins are translocated across the endoplasmic reticulum cotranslationally, in association with the ribosome–Sec61 translocon complex. Using a small domain in which tertiary structure can be reversibly controlled, a new study now demonstrates that folding of the nascent peptide within the compartment near the ribosome exit vestibule can influence translocation outcome.

Centromeric chromatin is established largely by epigenetic processes and involves the incorporation of histone H3 variant CENP-A. A new study implicates monoubiquitinated histone H2B (H2Bub1) in maintaining active centromeric chromatin in human cells and in fission yeast. H2Bub1 prevents heterochromatin formation at centromeres and promotes noncoding transcription, centromere integrity and accurate chromosomal segregation.

Voltage sensor domains (VSDs) transducer changes in the electrical field across cell membranes into conformational changes that alter the activation state of an effector domain. Structural and biophysical data on the VSD from Ci-VSP reveal the first view of this domain in the resting state, providing new insight into voltage-dependent structural transitions.

DNA polymerase μ promotes nonhomologous end joining (NHEJ) of DNA double-strand breaks. Crystal structures of truncated human DNA polymerase μ with and without a gapped DNA substrate provide the first structural evidence that the loop 1 domain is repositioned to permit template binding and that catalysis occurs without additional enzyme repositioning.

The 'dissolvasome', composed of TopIIIα, BLM and RMI proteins, coordinates DNA-helicase and DNA-topoisomerase activities to resolve double Holliday junctions (dHJs) generated during DNA recombination and repair. The first crystal structure of a human TopIIIα–Rmi1 subcomplex provides insights into how topoisomerase is stimulated to promote dHJ decatenation.

Bacteria use alternative sigma factors to direct transcription initiation from new sets of gene promoters in response to environmental stress. Complementary structural and biochemical analyses now reveal a new promoter-recognition mechanism that is the basis for the altered promoter specificity conferred by stress-responsive sigma factors.

The crystal structure of human RXRα–LXRβ heterodimer bound to its cognate DNA element, with agonists and a coactivator peptide, is now solved. The heterodimer shows an X-shaped organization, with DNA-binding and ligand-binding domains crossed, in contrast to previous crystal structures of nuclear receptor complexes.

Enterovirus HEV71 is responsible for recurring epidemics in developing countries. New structural analyses coupled with in silico docking methods have allowed for the generation of potent inhibitors of viral-envelope uncoating that block subsequent insertion of viral RNA into the host cell.