Volume 20 Issue 10, October 2013

Sodium-coupled glutamate transporters regulate excitatory signaling in the brain. A new crystal structure shows how the substrate induces changes in the binding pocket of an archaeal transporter homolog, providing new insights into the mechanism of transport.

Polycomb group (PcG) proteins function within Polycomb repressive complexes (PRCs), which modify histones and other proteins and silence target genes. This Review highlights new insights into the role of PcG proteins in gene regulation, specifically in controlling self-renewal and differentiation of embryonic stem cells, and into how PRCs are targeted to chromatin.

Although histone H3 Lys4 (H3K4) methylation is widely associated with gene activation, direct evidence for its causal role in transcription is lacking. New studies with the histone methyltransferase MLL2 in a cell-free transcription system now establish a direct causal role for MLL2-mediated H3K4 methylation in transcription and identify AKAP95 as a new modulator of H3K4 methylation.

In the eukaryotic 26S proteasome, a heterohexameric AAA+ complex unfolds substrates prior to degradation. The yeast unfoldase subunits have now been expressed in bacteria and reconstituted into active proteasomes in vitro. Mutations of catalytic and structural motifs in each individual subunits reveal that they play distinct roles in substrate processing, peptidase binding and gate opening.

How the activity of transposable elements is regulated is not well understood. A new study now shows that the Microprocessor complex, which is required for microRNA biogenesis, also recognizes and binds RNAs derived from human LINE-1, Alu and SVA retrotransposons and that it acts as a post-transcriptional repressor of mammalian retrotransposons in vivo.

p38α MAP kinase is activated by autophosphorylation, which is promoted by the protein TAB1 during myocardial ischemia and other stresses. Now cellular, biochemical and biophysical approaches reveal that TAB1 binds p38α's C-terminal kinase lobe and induces rearrangements within the activation segment that allow autophosphorylation in cis.

The cancer-associated D2723H mutation causes mislocalization of BRCA2 to the cytoplasm. New work shows that this mutation disrupts the interaction of BRCA2 with DSS1, unmasking a BRCA2 nuclear export signal within the DSS1 binding domain. This impairs nuclear retention of BRCA2 and, consequently, RAD51, suggesting that the intracellular localization of these factors may control their function in maintaining genome integrity.

Noncoding telomere repeat–containing RNA (TERRA) expressed from chromosome ends can form RNA-DNA hybrids at telomeres, but how this influences telomere length is unclear. Now, TERRA RNA-DNA hybrids are shown to promote telomere recombination and delay senescence in cells lacking telomerase, establishing a function for TERRA in telomere-length maintenance.

4C (chromosome conformation capture on chip) analyses using the clock-controlled Dbp gene as bait reveal the existence of circadian long-range interactions in mouse embryonic fibroblasts. The Dbp circadian interactome is dependent on a functional circadian clock and contains a number of clock-related DNA elements.

mRNAs have been shown to cross-talk with other mRNAs by serving as competing endogenous RNAs that 'sponge up' microRNAs. A report now claims a new, physiologically significant function for mRNAs that cross-talk through partially complementary Alu elements in the 3′ untranslated region. The Staufen1-mediated mRNA pathway targets both mRNAs in the duplex, provided that they are translated.

Equivalent mutations in the pseudokinase domain of Jak2 (V617F) and Jak1 (V658F) result in myeloproliferative disorders. Crystal structures of wild-type and the V658F mutant of human Jak1 spanning the pseudokinase domain and a segment of the SH2-PK linker now reveal the existence of a conformational switch that is stabilized by oncogenic mutations and favors activation.

Archaeal glutamate transporter homologs catalyze the coupled uptake of aspartate and sodium ions. A new crystal structure of Glt_Tk from Thermococcus kodakarensis shows the empty transporter oriented in the outward-facing conformation after substrate delivery, revealing how it is reset in preparation for another translocation cycle.

Individual microRNAs (miRNAs) can target many mRNAs that form networks of presumably cooperating genes. A new study now tests this idea by screening miRNAs and their targets in the context of dedifferentiation, or reprogramming, of mouse fibroblasts to induced pluripotent stem cells. These data establish two networks of miRNA-mRNA interactions that act together to suppress early stages of reprogramming.