Metal-ion coordination by U6 small nuclear RNA contributes to catalysis in the spliceosome

Introns are removed from nuclear messenger RNA precursors through two sequential phospho-transesterification reactions in a dynamic RNA-protein complex called the spliceosome. But whether splicing is catalysed by small nuclear RNAs in the spliceosome is unresolved. As the spliceosome is a metalloenzyme, it is important to determine whether snRNAs coordinate catalytic metals. Here we show that yeast U6 snRNA coordinates a metal ion that is required for the catalytic activity of the spliceosome. With Mg2+, U6 snRNA with a sulphur substitution for the pro-Rp or pro-Sp non-bridging phosphoryl oxygen of nucleotide U80 reconstitutes a fully assembled yet catalytically inactive spliceosome. Adding a thiophilic ion such as Mn2+ allows the first transesterification reaction to occur in the U6/sU80(Sp)- but not the U6/sU80(Rp)-reconstituted spliceosome. Mg2+ competitively inhibits the Mn2+-rescued reaction, indicating that the metal-binding site at U6/U80 exists in the wild-type spliceosome and that the site changes its metal requirement for activity in the Sp spliceosome. Thus, U6 snRNA contributes to pre-messenger RNA splicing through metal-ion coordination, which is consistent with RNA catalysis by the spliceosome.     

TERRA and hnRNPA1 orchestrate an RPA-to-POT1 switch on telomeric single-stranded DNA

Maintenance of telomeres requires both DNA replication and telomere 'capping' by shelterin. These two processes use two single-stranded DNA (ssDNA)-binding proteins, replication protein A (RPA) and protection of telomeres 1 (POT1). Although RPA and POT1 each have a critical role at telomeres, how they function in concert is not clear. POT1 ablation leads to activation of the ataxia telangiectasia and Rad3-related (ATR) checkpoint kinase at telomeres, suggesting that POT1 antagonizes RPA binding to telomeric ssDNA. Unexpectedly, we found that purified POT1 and its functional partner TPP1 are unable to prevent RPA binding to telomeric ssDNA efficiently. In cell extracts, we identified a novel activity that specifically displaces RPA, but not POT1, from telomeric ssDNA. Using purified protein, here we show that the heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) recapitulates the RPA displacing activity. The RPA displacing activity is inhibited by the telomeric repeat-containing RNA (TERRA) in early S phase, but is then unleashed in late S phase when TERRA levels decline at telomeres. Interestingly, TERRA also promotes POT1 binding to telomeric ssDNA by removing hnRNPA1, suggesting that the re-accumulation of TERRA after S phase helps to complete the RPA-to-POT1 switch on telomeric ssDNA. Together, our data suggest that hnRNPA1, TERRA and POT1 act in concert to displace RPA from telomeric ssDNA after DNA replication, and promote telomere capping to preserve genomic integrity.     

Interannual atmospheric variability forced by the deep equatorial Atlantic Ocean

Climate variability in the tropical Atlantic Ocean is determined by large-scale ocean-atmosphere interactions, which particularly affect deep atmospheric convection over the ocean and surrounding continents. Apart from influences from the Pacific El Ni?o/Southern Oscillation and the North Atlantic Oscillation, the tropical Atlantic variability is thought to be dominated by two distinct ocean-atmosphere coupled modes of variability that are characterized by meridional and zonal sea-surface-temperature gradients and are mainly active on decadal and interannual timescales, respectively. Here we report evidence that the intrinsic ocean dynamics of the deep equatorial Atlantic can also affect sea surface temperature, wind and rainfall in the tropical Atlantic region and constitutes a 4.5-yr climate cycle. Specifically, vertically alternating deep zonal jets of short vertical wavelength with a period of about 4.5?yr and amplitudes of more than 10?cm?s(-1) are observed, in the deep Atlantic, to propagate their energy upwards, towards the surface. They are linked, at the sea surface, to equatorial zonal current anomalies and eastern Atlantic temperature anomalies that have amplitudes of about 6?cm?s(-1) and 0.4?°C, respectively, and are associated with distinct wind and rainfall patterns. Although deep jets are also observed in the Pacific and Indian oceans, only the Atlantic deep jets seem to oscillate on interannual timescales. Our knowledge of the persistence and regularity of these jets is limited by the availability of high-quality data. Despite this caveat, the oscillatory behaviour can still be used to improve predictions of sea surface temperature in the tropical Atlantic. Deep-jet generation and upward energy transmission through the Equatorial Undercurrent warrant further theoretical study.     

A candidate redshift z ≈ 10 galaxy and rapid changes in that population at an age of 500 Myr

Searches for very-high-redshift galaxies over the past decade have yielded a large sample of more than 6,000 galaxies existing just 900-2,000?million years (Myr) after the Big Bang (redshifts 6?>?z?>?3; ref. 1). The Hubble Ultra Deep Field (HUDF09) data have yielded the first reliable detections of z?≈?8 galaxies that, together with reports of a γ-ray burst at z?≈?8.2 (refs 10, 11), constitute the earliest objects reliably reported to date. Observations of z?≈?7-8 galaxies suggest substantial star formation at z?>?9-10 (refs 12, 13). Here we use the full two-year HUDF09 data to conduct an ultra-deep search for z?≈?10 galaxies in the heart of the reionization epoch, only 500?Myr after the Big Bang. Not only do we find one possible z?≈?10 galaxy candidate, but we show that, regardless of source detections, the star formation rate density is much smaller (～10%) at this time than it is just ～200?Myr later at z?≈?8. This demonstrates how rapid galaxy build-up was at z?≈?10, as galaxies increased in both luminosity density and volume density from z?≈?10 to z?≈?8. The 100-200?Myr before z?≈?10 is clearly a crucial phase in the assembly of the earliest galaxies.     

A synthetic homing endonuclease-based gene drive system in the human malaria mosquito

Genetic methods of manipulating or eradicating disease vector populations have long been discussed as an attractive alternative to existing control measures because of their potential advantages in terms of effectiveness and species specificity. The development of genetically engineered malaria-resistant mosquitoes has shown, as a proof of principle, the possibility of targeting the mosquito's ability to serve as a disease vector. The translation of these achievements into control measures requires an effective technology to spread a genetic modification from laboratory mosquitoes to field populations. We have suggested previously that homing endonuclease genes (HEGs), a class of simple selfish genetic elements, could be exploited for this purpose. Here we demonstrate that a synthetic genetic element, consisting of mosquito regulatory regions and the homing endonuclease gene I-SceI, can substantially increase its transmission to the progeny in transgenic mosquitoes of the human malaria vector Anopheles gambiae. We show that the I-SceI element is able to invade receptive mosquito cage populations rapidly, validating mathematical models for the transmission dynamics of HEGs. Molecular analyses confirm that expression of I-SceI in the male germline induces high rates of site-specific chromosomal cleavage and gene conversion, which results in the gain of the I-SceI gene, and underlies the observed genetic drive. These findings demonstrate a new mechanism by which genetic control measures can be implemented. Our results also show in principle how sequence-specific genetic drive elements like HEGs could be used to take the step from the genetic engineering of individuals to the genetic engineering of populations.