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Genome-wide analysis of human variation in 25 diverse groups from India reveals two ancient populations, genetically divergent, that are ancestral to most Indians today. Traditionally upper caste and Indo-European speakers tend to be descended from a group that is genetically close to Middle Easterners, Central Asians and Europeans. The other group, the 'Ancestral South Indians', does not appear to be close to any group outside the subcontinent.
Polycomb group proteins are involved in the epigenetic maintenance of repressive chromatin states, with the gene-silencing activity of the Polycomb repressive complex 2 (PRC2) dependent on its ability to trimethylate lysine 27 of histone H3. The carboxy-terminal domain of the EED subunit of the complex is now shown to specifically bind to histone tails carrying trimethyl-lysine residues associated with repressive chromatin marks, leading to activation of the methyltransferase activity of PRC2.
Deregulated Wnt pathway activity has been implicated in many cancers, making this pathway an attractive target for anticancer therapies. Here, a small molecule inhibitor of the Wnt pathway is identified and its direct target and mechanism of action are characterized, providing new insights into the physiological regulation of the Wnt pathway and new possibilities for targeted Wnt pathway therapeutics.
Proteasome structure is extensively conserved across a broad range of organisms, so it is not surprising that inhibitors of all chemical classes tested have blocked both eukaryotic and prokaryotic proteasomes. However, certain oxathiazol-2-one compounds are now shown to kill non-replicating Mycobacterium tuberculosis and act as selective inhibitors of the M. tuberculosis proteasome while largely sparing the human homologue.
A known regulator of prostate epithelial differentiation, Nkx3-1, is shown here to mark a stem cell population that functions during prostate regeneration. Furthermore, in mice in which the Pten tumour suppressor gene is deleted in a group of rare cells that express Nkx3-1 in the absence of testicular androgens, termed CARN cells, there is rapid carcinoma formation after andogen-mediated regeneration. These observations indicate that prostate cancer can originate in CARN cells.
The mitochondrial genome is of maternal origin and mutations in mitochondrial DNA are the cause of many human diseases. The efficient replacement of the mitochondrial genome in mature non-human primate oocytes is now demonstrated. This approach may offer a reproductive option to prevent the transmission of diseases caused by mutations in mitochondrial DNA in affected families.
The levels of messenger RNA are determined by the rates of RNA decay and transcription, but although the details of transcriptional regulation are increasingly understood, the mechanism(s) controlling mRNA decay remain unclear. In yeast, it is hypothesized that ribosomes must be removed from mRNA before transcripts are destroyed. However, here it is shown that decay takes place while mRNAs are associated with actively translating ribosomes, allowing the last translocating ribosome to complete translation.
Accumulating evidence suggests that the human telomerase reverse transcriptase catalytic subunit (TERT) has a role in cell physiology independent to that of elongating telomeres. Here it is shown to interact with RMRP, a gene that is mutated in the syndrome cartilage–hair hypoplasia, to form a distinct ribonucleoprotein complex that has RNA-dependent RNA polymerase (RdRP) activity and produces double-stranded RNAs that can be processed into small interfering RNAs.
After transcription and processing, transfer RNAs must be exported from the nucleus to the cytoplasm, where translation occurs. This process is mediated by a dedicated nucleo-cytoplasmic transport factor called Xpot. Here, the structure of Schizosaccharomyces pombe Xpot is reported, unbound and in complex with both tRNA and another factor required for transport, RanGTP.
Nearly 5% of membrane proteins are 'tail-anchored' to the endoplasmic reticulum by a single carboxy-terminal transmembrane domain. These tail-anchored proteins are targeted post-translationally by the ATPase Get3, but the mechanism of recognition and targeting by Get3 is not known. Here, the crystal structures of yeast Get3 in a nucleotide-free 'open' state and a nucleotide-bound 'closed' state are presented.
Single-stranded RNA viruses are responsible for the common cold, cancer, AIDS and other serious health threats. The genomes of these viruses form conserved secondary structures that have functional and regulatory roles, but most potential regulatory elements in viral RNA genomes remain uncharacterized. Here however, the structure of an entire HIV-1 genome at single nucleotide resolution is reported.
The contribution of changes in cis-regulatory elements or trans-acting factors to differences in gene expression between species is not well understood. Here it is found that, in transgenic mice containing the human β-globin locus, the expression of BCL11A differs between mouse and human and is a critical mediator of species-divergent globin switching.
P2X receptors are ATP-gated cation channels that are implicated in diverse physiological processes, from synaptic transmission to inflammation to the sensing of taste and pain. The crystal structure of the zebrafish P2X4 channel is now solved in its closed state, revealing some of the molecular underpinnings of ligand-binding, cation entry and channel gating.
Like P2X receptors, acid-sensing ion channels are trimeric in structure; however, they belong to an entirely different family. Here, the structure of an acid-sensing ion channel is presented and compared to the structure of P2X4, suggesting that these functionally distinct channels use similar mechanistic principles.
The human genome contains numerous types of repeated 'at risk' sequences that can cause genomic rearrangements and instability. Various proteins are used to ensure that this occurs very infrequently. Here, a comprehensive analysis of the factors involved in suppressing gross chromosomal rearrangements in Saccharomyces cerevisiae shows that there are distinct pathways for suppressing rearrangements mediated by single copy sequences versus repetitive 'at risk' sequences.
The mechanism by which the tubular architecture of the endoplasmic reticulum (ER) is maintained is unclear, although homotypic membrane fusion is known to be required for ER biogenesis and maintenance and this is dependent on GTP hydrolysis. Here it is demonstrated that loss of the GTPase Atlastin in Drosophila causes ER fragmentation, whereas its overexpression induces enlargement of ER profiles.
The high harmonic emission that accompanies the recombination of an electron with its parent molecular ion in an intense laser field provides a snapshot of the structure and dynamics of the recombining system. Experiments on CO2 molecules now show how to extract information from the properties of the emitted light about the underlying multi-electron dynamics with sub-Ångström spatial resolution and attosecond temporal resolution
Escherichia coli DNA polymerase (pol) V is involved in the mutagenic process of limited DNA synthesis across a DNA lesion, but the molecular composition of mutagenically active pol V and the importance of the RecA nucleoprotein filament RecA* have remained unclear. The biochemical role of RecA* is now defined.
Schistosoma mansoni and Schistosoma japonicum are the pathogenic agents that cause the tropical disease schistosomiasis. Here, and in an accompanying paper, the genomes of these two flatworms are sequenced and analysed. The results provide insights into the molecular architecture and host interactions of the flatworms, as well as avenues for future development of targeted interventions for schistosomiasis.
Schistosoma mansoni and Schistosoma japonicum are the pathogenic agents that cause the tropical disease schistosomiasis. Here, and in an accompanying paper, the genomes of these two flatworms are sequenced and analysed. The results provide insights into the molecular architecture and host interactions of the flatworms, as well as avenues for future development of targeted interventions for schistosomiasis.
