The Ccr4-Not Complex Interacts with the mRNA Export Machinery

The Ccr4-Not complex is a key eukaryotic regulator of gene transcription and cytoplasmic mRNA degradation. Whether this complex also affects aspects of post-transcriptional gene regulation, such as mRNA export, remains largely unexplored. Human Caf1 (hCaf1), a Ccr4-Not complex member, interacts with and regulates the arginine methyltransferase PRMT1, whose targets include RNA binding proteins involved in mRNA export. However, the functional significance of this regulation is poorly understood.Here we demonstrate using co-immunoprecipitation approaches that Ccr4-Not subunits interact with Hmt1, the budding yeast ortholog of PRMT1. Furthermore, using genetic and biochemical approaches, we demonstrate that Ccr4-Not physically and functionally interacts with the heterogenous nuclear ribonucleoproteins (hnRNPs) Nab2 and Hrp1, and that the physical association depends on Hmt1 methyltransferase activity. Using mass spectrometry, co-immunoprecipitation and genetic approaches, we also uncover physical and functional interactions between Ccr4-Not subunits and components of the nuclear pore complex (NPC) and we provide evidence that these interactions impact mRNA export.Taken together, our findings suggest that Ccr4-Not has previously unrealized functional connections to the mRNA processing/export pathway that are likely important for its role in gene expression. These results shed further insight into the biological functions of Ccr4-Not and suggest that this complex is involved in all aspects of mRNA biogenesis, from the regulation of transcription to mRNA export and turnover

Cosmology intertwined: A review of the particle physics, astrophysics, and cosmology associated with the cosmological tensions and anomalies

The standard Cold Dark Matter (CDM) cosmological model provides a good description of a wide range of astrophysical and cosmological data. However, there are a few big open questions that make the standard model look like an approximation to a more realistic scenario yet to be found. In this paper, we list a few important goals that need to be addressed in the next decade, taking into account the current discordances between the different cosmological probes, such as the disagreement in the value of the Hubble constant H0, the σ8–S8 tension, and other less statistically significant anomalies. While these discordances can still be in part the result of systematic errors, their persistence after several years of accurate analysis strongly hints at cracks in the standard cosmological scenario and the necessity for new physics or generalisations beyond the standard model. In this paper, we focus on the 5.0 σ tension between the Planck CMB estimate of the Hubble constant H0 and the SH0ES collaboration measurements. After showing the H0 evaluations made from different teams using different methods and geometric calibrations, we list a few interesting new physics models that could alleviate this tension and discuss how the next decade’s experiments will be crucial. Moreover, we focus on the tension of the Planck CMB data with weak lensing measurements and redshift surveys, about the value of the matter energy density m, and the amplitude or rate of the growth of structure (σ8, f σ8). We list a few interesting models proposed for alleviating this tension, and we discuss the importance of trying to fit a full array of data with a single model and not just one parameter at a time. Additionally, we present a wide range of other less discussed anomalies at a statistical significance level lower than the H0–S8 tensions which may also constitute hints towards new physics, and we discuss possible generic theoretical approaches that can collectively explain the non-standard nature of these signals. Finally, we give an overview of upgraded experiments and next-generation space missions and facilities on Earth that will be of crucial importance to address all these open questions

DUSEL Theory White Paper

The NSF has chosen the site for the Deep Underground Science and Engineering Laboratory (DUSEL) to be in Lead, South Dakota. In fact, the state of South Dakota has already stepped up to the plate and contributed its own funding for the proposed lab, see http://www.sanfordlaboratoryathomestake.org/index.html. The final decision by NSF for funding the Initial Suite of Experiments for DUSEL will be made early in 2009. At that time the NSF Science Board must make a decision. Of order 200 experimentalists have already expressed an interest in performing experiments at DUSEL. In order to assess the interest of the theoretical community, the Center for Cosmology and Astro-Particle Physics (CCAPP) at The Ohio State University (OSU) organized a 3-day DUSEL Theory Workshop in Columbus, Ohio from April 4 - 6, 2008. The workshop focused on the scientific case for six proposed experiments for DUSEL: long baseline neutrino oscillations, proton decay, dark matter, astrophysical neutrinos, neutrinoless double beta decay and N-Nbar oscillations. The outcome of this workshop is the DUSEL Theory White paper addressing the scientific case at a level which may be useful in the decision making process for policy makers at the NSF and in the U.S. Congress. In order to assess the physics interest in the DUSEL project we have posted the DUSEL Theory White paper on the following CCAPP link http://ccapp.osu.edu/whitepaper.html . Please read the white paper and, if you are interested, use the link to show your support by co-signing the white paper

DUSEL Theory White Paper

The NSF has chosen the site for the Deep Underground Science and Engineering Laboratory (DUSEL) to be in Lead, South Dakota. In fact, the state of South Dakota has already stepped up to the plate and contributed its own funding for the proposed lab, see http://www.sanfordlaboratoryathomestake.org/index.html. The final decision by NSF for funding the Initial Suite of Experiments for DUSEL will be made early in 2009. At that time the NSF Science Board must make a decision. Of order 200 experimentalists have already expressed an interest in performing experiments at DUSEL. In order to assess the interest of the theoretical community, the Center for Cosmology and Astro-Particle Physics (CCAPP) at The Ohio State University (OSU) organized a 3-day DUSEL Theory Workshop in Columbus, Ohio from April 4 - 6, 2008. The workshop focused on the scientific case for six proposed experiments for DUSEL: long baseline neutrino oscillations, proton decay, dark matter, astrophysical neutrinos, neutrinoless double beta decay and N-Nbar oscillations. The outcome of this workshop is the DUSEL Theory White paper addressing the scientific case at a level which may be useful in the decision making process for policy makers at the NSF and in the U.S. Congress. In order to assess the physics interest in the DUSEL project we have posted the DUSEL Theory White paper on the following CCAPP link http://ccapp.osu.edu/whitepaper.html . Please read the white paper and, if you are interested, use the link to show your support by co-signing the white paper

Recognition of distinct RNA motifs by the clustered CCCH zinc fingers of neuronal protein Unkempt

Unkempt is an evolutionarily conserved RNA-binding protein that regulates translation of its target genes and is required for the establishment of the early bipolar neuronal morphology. Here we determined the X-ray crystal structure of mouse Unkempt and show that its six CCCH zinc fingers (ZnFs) form two compact clusters, ZnF–3 and ZnF4–6, that recognize distinct trinucleotide RNA substrates. Both ZnF clusters adopt a similar overall topology and use distinct recognition principles to target specific RNA sequences. Structure-guided point mutations reduce the RNA binding affinity of Unkempt both in vitro and in vivo, ablate Unkempt’s translational control and impair the ability of Unkempt to induce a bipolar cellular morphology. Our study unravels a new mode of RNA sequence recognition by clusters of CCCH ZnFs that is critical for post-transcriptional control of neuronal morphology

Fungal Pre-mRNA 3′-End Processing

3' end processing of messenger RNAs (mRNAs) is not only an essential step in eukaryotic gene expression, but it also impacts many other aspects of mRNA maturation and decay. A large portion of eukaryotic genes produce multiple mRNAs with different 3' ends through alternative cleavage/polyadenylation (APA). mRNA 3' processing and especially APA has been increasingly recognized as an important mechanism for gene regulation. Much of what we currently know about eukaryotic mRNA 3' processing came from studies using the genetically tractable yeast systems. Here we review the fungal mRNA 3' processing system by describing both the evolutionarily conserved mechanisms as well as the fungus-specific features