The Role of Sub1/PC4 in Transcription Elongation Depends on the C-Terminal Region and Is Independent of the ssDNA Binding Domain.

Sub1 (ScSub1) has been defined as a transcriptional stimulatory protein due to its homology to the ssDNA binding domain (ssDBD) of human PC4 (hPC4). Recently, PC4/Sub1 orthologues have been elucidated in eukaryotes, prokaryotes, and bacteriophages with functions related to DNA metabolism. Additionally, ScSub1 contains a unique carboxyl-terminal region (CT) of unknown function up to date.

Structural basis of Nrd1-Nab3 heterodimerization.

Heterodimerization of RNA binding proteins Nrd1 and Nab3 is essential to communicate the RNA recognition in the nascent transcript with the Nrd1 recognition of the Ser-phosphorylated Rbp1 C-terminal domain in RNA polymerase II. The structure of a Nrd1-Nab3 chimera reveals the basis of heterodimerization, filling a missing gap in knowledge of this system. The free form of the Nrd1 interaction domain of Nab3 (NRID) forms a multi-state three-helix bundle that is clamped in a single conformation upon complex formation with the Nab3 interaction domain of Nrd1 (NAID).

Regulation of Eukaryotic RNAPs Activities by Phosphorylation.

Evolutionarily conserved kinases and phosphatases regulate RNA polymerase II (RNAPII) transcript synthesis by modifying the phosphorylation status of the carboxyl-terminal domain (CTD) of Rpb1, the largest subunit of RNAPII. Proper levels of Rpb1-CTD phosphorylation are required for RNA co-transcriptional processing and to coordinate transcription with other nuclear processes, such as chromatin remodeling and histone modification. Whether other RNAPII subunits are phosphorylated and influences their role in gene expression is still an unanswered question.

Validation of kinetic modeling of [O]HO PET using an image derived input function on hybrid PET/MRI.

In present study we aimed to validate the use of image-derived input functions (IDIF) in the kinetic modeling of cerebral blood flow (CBF) measured by [O]HO PET by comparing with the accepted reference standard arterial input function (AIF). Additional comparisons were made to mean cohort AIF and CBF values acquired by methodologically independent phase-contrast mapping (PCM) MRI. Using hybrid PET/MRI an IDIF was generated by measuring the radiotracer concentration in the internal carotid arteries and correcting for partial volume effects using the intravascular volume measured from MRI-angiograms.

Assessing potential aquatic toxicity of airport runoff using physicochemical parameters and Lemna gibba and Aliivibrio fischeri bioassays.

A critical problem derived from airport operations is the environmental impact of runoff water. Airport runoff includes a complex mixture of pollutants, e.g.

RNA polymerase II phosphorylation and gene looping: new roles for the Rpb4/7 heterodimer in regulating gene expression.

In eukaryotes, cellular RNAs are produced by three nuclear RNA polymerases (RNAPI, II, and III), which are multisubunit complexes. They share structural and functional features, although they are specialized in the synthesis of specific RNAs. RNAPII transcribes the vast majority of cellular RNAs, including mRNAs and a large number of noncoding RNAs.

RNA polymerase II plays an active role in the formation of gene loops through the Rpb4 subunit.

Gene loops are formed by the interaction of initiation and termination factors occupying the distal ends of a gene during transcription. RNAPII is believed to affect gene looping indirectly owing to its essential role in transcription. The results presented here, however, demonstrate a direct role of RNAPII in gene looping through the Rpb4 subunit.

Genetic analyses led to the discovery of a super-active mutant of the RNA polymerase I.

Most transcriptional activity of exponentially growing cells is carried out by the RNA Polymerase I (Pol I), which produces a ribosomal RNA (rRNA) precursor. In budding yeast, Pol I is a multimeric enzyme with 14 subunits. Among them, Rpa49 forms with Rpa34 a Pol I-specific heterodimer (homologous to PAF53/CAST heterodimer in human Pol I), which might be responsible for the specific functions of the Pol I.

The telomeric Cdc13-Stn1-Ten1 complex regulates RNA polymerase II transcription.

Specialized telomeric proteins have an essential role in maintaining genome stability through chromosome end protection and telomere length regulation. In the yeast Saccharomyces cerevisiae, the evolutionary conserved CST complex, composed of the Cdc13, Stn1 and Ten1 proteins, largely contributes to these functions. Here, we report genetic interactions between TEN1 and several genes coding for transcription regulators.

Structural basis of RNA polymerase I stalling at UV light-induced DNA damage.

RNA polymerase I (Pol I) transcribes ribosomal DNA (rDNA) to produce the ribosomal RNA (rRNA) precursor, which accounts for up to 60% of the total transcriptional activity in growing cells. Pol I monitors rDNA integrity and influences cell survival, but little is known about how this enzyme processes UV-induced lesions. We report the electron cryomicroscopy structure of Pol I in an elongation complex containing a cyclobutane pyrimidine dimer (CPD) at a resolution of 3.

Subclinical depressive symptoms during late midlife and structural brain alterations: A longitudinal study of Danish men born in 1953.

We explored whether depressive symptoms measured three times during midlife were associated with structural brain alterations quantified using magnetic resonance imaging measurements of volume, cortical thickness, and intensity texture. In 192 men born in 1953 with depressive symptoms measured at age 51, 56, and 59 years, magnetic resonance imaging was performed at age 59. All data processing was performed using the Freesurfer software package except for the texture-scores that were computed using in-house software.

The structure of transcription termination factor Nrd1 reveals an original mode for GUAA recognition.

Transcription termination of non-coding RNAs is regulated in yeast by a complex of three RNA binding proteins: Nrd1, Nab3 and Sen1. Nrd1 is central in this process by interacting with Rbp1 of RNA polymerase II, Trf4 of TRAMP and GUAA/G terminator sequences. We lack structural data for the last of these binding events.

Sub1 and RNAPII, until termination does them part.

Sub1 was initially identified as a coactivator factor with a role during transcription initiation. However, over the last years, many evidences showed that it influences processes downstream during mRNA biogenesis, such as elongation, termination, and RNAPII phosphorylation. The recent discover that Sub1 directly interacts with the RNAPII stalk adds new insights into how it achieves all these tasks.

Sub1/PC4, a multifaceted factor: from transcription to genome stability.

Yeast Sub1 and human PC4, two DNA-binding proteins, were originally identified as transcriptional coactivators with a role during transcription preinitiation/initiation. Indeed, Sub1 is a PIC component, and both PC4 and Sub1 also influence the initiation-elongation transition. Moreover, in the specific case of Sub1, it has been clearly reported that it influences processes downstream during mRNA biogenesis, such as transcription elongation, splicing and termination, and even RNAPII phosphorylation/dephosphorylation.

The dynamic assembly of distinct RNA polymerase I complexes modulates rDNA transcription.

Cell growth requires synthesis of ribosomal RNA by RNA polymerase I (Pol I). Binding of initiation factor Rrn3 activates Pol I, fostering recruitment to ribosomal DNA promoters. This fundamental process must be precisely regulated to satisfy cell needs at any time.

Sub1 contacts the RNA polymerase II stalk to modulate mRNA synthesis.

Biogenesis of messenger RNA is critically influenced by the phosphorylation state of the carboxy-terminal domain (CTD) in the largest RNA polymerase II (RNAPII) subunit. Several kinases and phosphatases are required to maintain proper CTD phosphorylation levels and, additionally, several other proteins modulate them, including Rpb4/7 and Sub1. The Rpb4/7 heterodimer, constituting the RNAPII stalk, promote phosphatase functions and Sub1 globally influences CTD phosphorylation, though its mechanism remains mostly unknown.

Prostate cancer perspectives after chaarted: Optimizing treatment sequence.

Prostate cancer is the most frequent cancer amongst men. Until recently, only two therapeutic options, initial androgen-deprivation therapy in patients without castration-resistant prostate cancer, with addition of docetaxel when the disease becomes castration-resistant, were considered as standard. In the last years, new drugs (abiraterone, enzalutamide, Ra-223, Sipuleucel) have been developed for prostate cancer treatment with important advantages in safety and efficacy.

Atmospheric CO enrichment and drought stress modify root exudation of barley.

Rising CO concentrations associated with drought stress is likely to influence not only aboveground growth, but also belowground plant processes. Little is known about root exudation being influenced by elements of climate change. Therefore, this study wanted to clarify whether barley root exudation responds to drought and CO enrichment and whether this reaction differs between an old and a recently released malting barley cultivar.

Potential toxic effects of aircraft de-icers and wastewater samples containing these compounds.

One of the major problems of airport operation is the impact of pollution caused by runoff waters. Runoff waters at an airport may contain high concentrations of different contaminants resulting from various activities of its operation. High quantities of aircraft de-icing/anti-icing fluids are used annually at airports worldwide.

Enzalutamide: a new prostate cancer targeted therapy against the androgen receptor.

Enzalutamide (MDV3100), an androgen receptor-signalling inhibitor, represents the most recent compound added to the therapeutic armamentarium for the treatment of metastatic castration-resistant prostate cancer (mCRPC) who progressed to docetaxel. The anti-tumour activity and safety of enzalutamide has been demonstrated in a phase III clinical trial, showing a benefit in overall survival, which was the primary endpoint. There are no head-to-head studies comparing the different treatment options in this subset of patients.

Rpb4/7 facilitates RNA polymerase II CTD dephosphorylation.

The Rpb4 and Rpb7 subunits of eukaryotic RNA polymerase II (RNAPII) participate in a variety of processes from transcription, DNA repair, mRNA export and decay, to translation regulation and stress response. However, their mechanism(s) of action remains unclear. Here, we show that the Rpb4/7 heterodimer in Saccharomyces cerevisiae plays a key role in controlling phosphorylation of the carboxy terminal domain (CTD) of the Rpb1 subunit of RNAPII.

Sub1 associates with Spt5 and influences RNA polymerase II transcription elongation rate.

The transcriptional coactivator Sub1 has been implicated in several steps of mRNA metabolism in yeast, such as the activation of transcription, termination, and 3'-end formation. In addition, Sub1 globally regulates RNA polymerase II phosphorylation, and most recently it has been shown that it is a functional component of the preinitiation complex. Here we present evidence that Sub1 plays a significant role in transcription elongation by RNA polymerase II (RNAPII).