Articles in 2010

A new approach is used to target BET family bromodomains which are found in transcriptional regulators where they mediate the recognition of acetyl-lysine chromatin marks. Structural data reveal how the compound JQ1 binds to the bromodomain of BRD4. BRD4 has been implicated in a subtype of human squamous carcinomas, and JQ1 is found to inhibit the growth of BRD4 dependent tumours in mouse models.

Salmonella enterica serotype Typhimurium causes acute gut inflammation, which promotes the growth of the pathogen through unknown mechanisms. It is now shown that the reactive oxygen species generated during inflammation react with host-derived sulphur compounds to produce tetrathionate, which the pathogen uses as a terminal electron acceptor to support its growth. The ability to use tetrathionate provides the pathogen with a competitive advantage over bacteria that lack this property.

The evolutionary origin of the human malaria parasite Plasmodium falciparum has been much debated. Genetic analysis of a large number of faecal samples from wild-living African apes now shows that Plasmodium parasites from Western gorillas are most closely related to the human parasite. The data suggest that human P. falciparum evolved from a gorilla parasite after a single host transfer event.

Biological systems avoid molecular noise using feedback loops controlling RNA or protein synthesis, but these reactions rely on the stochastic birth and death of molecules. These authors use control and information theory to show that making a genetic network twice as accurate takes 16 times more signalling steps. Nature must therefore call on brute-force solutions to maintain accuracy, and hence does so only when noise suppression is absolutely vital.

In the ubiquitin–proteasome system, substrates destined for destruction are modified with ubiquitin chains and then degraded by the proteasome. These authors reveal a regulatory mechanism in which proteasomal activity is modulated by the length of ubiquitin chains in human cells. They find that deubiquitinating enzyme USP14 can inhibit the degradation of ubiquitin-conjugated substrates by trimming ubiquitin chains, and that stimulation of proteasome activity may be used to reduce the levels of toxic proteins in cells.

Neurons of the peripheral nervous system need survival factors to prevent their death during development. Most in the central nervous system do not. Why are peripheral neurons so needy? Here it is shown that the neurotrophin receptors TrkA and TrkC, expressed at high levels by many peripheral nervous system neurons, behave as dependence receptors: they instruct neurons to die if there is no ligand around. By contrast, TrkB, expressed mainly in the central nervous system, does not signal death in the absence of ligand.

Here, the analysis of 'HapMap 3' is reported — a public data set of genomic variants in human populations. The resource integrates common and rare single nucleotide polymorphisms (SNPs) and copy number polymorphisms (CNPs) from 11 global populations, providing insights into population-specific differences among variants. It also demonstrates the feasibility of imputing newly discovered rare SNPs and CNPs.

The causes of the neurodegenerative disease amyotrophic lateral sclerosis (ALS) are poorly understood, although the protein TDP-43 seems to be involved. These authors show that the polyglutamine-containing protein ataxin 2 interacts with TDP-43 and is a potent modifier of TDP-43 toxicity. Moreover, intermediate-length polyglutamine expansions in the ataxin 2 gene significantly associate with ALS. These data establish the ataxin 2 gene as a new and relatively common ALS disease susceptibility gene.

These authors show that changes in seismic anisotropy with depth across the stable part of North America reveal the presence of two lithospheric layers. The top layer, which is chemically depleted, is ∼150 km thick under the ancient core of the continent and tapers out along its younger borders. The bottom of the lithosphere is relatively flat, in agreement with the presence of a thermal conductive root that subsequently formed around the depleted chemical layer.

Adenovirus E1B-55k targets transcription factor p53 for degradation and is thought to be critical for p53 inactivation during adenovirus replication. Indeed, mutant viruses lacking E1B-55k have been tested as viral cancer therapies selective for p53-positive tumours. These authors find another adenoviral protein, E4-ORF3, to inactivate p53 independently of E1B-55k by means of a chromatin-silencing mechanism that prevents access of p53 to its DNA target sites.

The small GTPase Ran regulates nuclear transport and cell division by creating a gradient of RanGTP around chromosomes. The RCC1 protein recruits Ran to nucleosomes and activates Ran's nucleotide exchange activity. Here, the crystal structure of the complex between RCC1 and the nucleosome core particle is revealed. It provides an atomic view of how a chromatin protein interacts with the histone and DNA components of the nucleosome.

The two hereditary breast cancer susceptibility genes, BRCA1 and BRCA2, have roles in responding to DNA damage. When they are mutated or absent, genomic instability, a contributory factor to cancer development, results. Studies of BRCA2 have been hampered by its large size, which makes purification of the full-length protein challenging. These authors report the first in vitro characterization of full-length BRCA2 and delineate the different ways by which BRCA2 facilitates RAD51-mediated homologous recombination.

When double-strand breaks occur in eukaryotic DNA, the chromatin that protects and organizes the genome must be removed from the vicinity of the break to allow repair factors to bind. Such chromatin displacement involves the addition of ubiquitin groups to histone proteins near the break by the ubiquitin ligases RNF8 and RNF168. Here it is shown that the enzyme OTUB1 prevents RNF168-dependent poly-ubiquitination. Pharmacological targeting of this process might enhance the DNA damage response.

Gene activation may involve the formation of a DNA loop that connects enhancer-bound transcription factors with the transcription apparatus at the core promoter. But this process is not well understood. Here, two proteins, mediator and cohesin, are shown to connect the enhancers and core promoters of active genes in embryonic stem cells. These proteins seem to generate cell-type-specific DNA loops linked to the gene expression program of each cell.

MicroRNAs are known to affect the levels of both messenger RNA (mRNA) and protein. But as protein production is dependent on the presence of mRNA, it was not clear what the relative contributions of microRNA-mediated mRNA cleavage and translational repression were. These authors have parsed out the two mechanisms, and unexpectedly find that microRNAs function primarily by affecting mRNA levels rather than their translation. This suggests a reassessment of many previous conclusions is necessary.

The identity of the cells that form the haematopoietic stem cell (HSC) niche in bone marrow has been unclear. These authors identify nestin-expressing mesenchymal stem cells as niche-forming cells. These nestin-expressing cells show a close physical association with HSCs and express high levels of genes involved in HSC maintenance, and their depletion reduces bone marrow homing of haematopoietic progenitors.

The uptake of calcium by mitochondria has a central role in cell physiology, and an imbalance can trigger cell death. Now the first protein that is localized to the mitochondrion and is specifically required for calcium uptake has been identified. This protein, mitochondrial calcium uptake 1 (MICU1), represents the founding member of a set of proteins required for high-capacity calcium uptake. Its discovery should aid in the full molecular characterization of the mitochondrial calcium uptake pathways.

These authors report and analyse the draft genome sequence of the demosponge Amphimedon queenslandica. Sponges lie on the earliest branching lineage in the animal kingdom and thus have been important in studies of the origins of multicellularity. Comparative genomic analyses presented here provide significant insights into evolutionary origins of genes and pathways related to the hallmarks of metazoan multicellularity and to cancer biology.

A non-coding polymorphism at a locus associated with myocardial infarction in humans creates a CCAAT/enhancer binding protein transcription factor binding site and alters the hepatic expression of the SORT1 gene. These authors show that modulating Sort1 levels in mouse liver alters levels of plasma low-density lipoprotein cholesterol and very low-density lipoprotein, potentially explaining why polymorphisms at this locus are associated with heart disease.

Lipid concentration in the serum is one of the most important risk factors for coronary artery disease and can be targeted for therapeutic intervention. A genome-wide association study in >100,000 individuals of European ancestry now finds 95 significantly associated loci that also affect lipid traits in non-European populations. Among associated loci are those involved in cholesterol metabolism, known targets of cholesterol-lowering drugs and those that contribute to normal variation in lipid traits and to extreme lipid phenotypes.