The Proteins PDIP3 and ZC11A Associate with the Human TREX Complex in an ATP-Dependent Manner and Function in mRNA Export

The conserved TREX complex, which contains UAP56, Aly, CIP29, and the multi-subunit THO complex, functions in mRNA export. Recently, several putative new components of the human TREX complex were identified by mass spectrometry. Here, we investigated the function of two of these, PDIP3 and ZC11A. Our data indicate that both of these proteins are components of a common TREX complex and function in mRNA export. Recently, we found that both CIP29 and Aly associate with the DEAD box helicase UAP56 and with the TREX complex in an ATP-dependent manner. We now show that this is also the case for PDIP3 and ZC11A. Thus, together with previous work, our data indicate that the TREX complex participates in multiple ATP-dependent interactions

TREX exposes the RNA binding domain of Nxf1 to enable mRNA export

The metazoan TREX complex is recruited to mRNA during nuclear RNA processing and functions in exporting mRNA to the cytoplasm. Nxf1 is an mRNA export receptor, which binds processed mRNA and transports it through the nuclear pore complex. At present, the relationship between TREX and Nxf1 is not understood. Here we show that Nxf1 uses an intramolecular interaction to inhibit its own RNA binding activity. When the TREX subunits Aly and Thoc5 make contact with Nxf1, Nxf1 is driven into an open conformation, exposing its RNA binding domain, allowing RNA binding. Moreover, the combined knockdown of Aly and Thoc5 drastically reduces the amount of Nxf1 bound to mRNA in vivo and also causes a severe mRNA export block. Together, our data indicate that TREX provides a license for mRNA export by driving Nxf1 into a conformation capable of binding mRNA

Ultra-precise Masses and Magnitudes for the Gliese 268 M-dwarf Binary

Recent advances in astrometry using interferometry and precision radial velocity techniques combined allow for a significant improvement in the precision of masses of M‐dwarf stars in visual systems. We report recent astrometric observations of Gliese 268, an M‐dwarf binary with a 10.4 day orbital period, with the IOTA interferometer and radial velocity observations with the ELODIE instrument. Combining these measurements leads to preliminary masses of the constituent stars with uncertainties of 0.4%. The masses of the components are 0.22596±0.00084 M_⊙ for the primary and 0.19230±0.00071 M_⊙ for the secondary. The system parallax is determined by these observations to be 0.1560±.0030 arcsec (2.0% uncertainty) and is within Hipparcos error bars (0.1572±.0033). We tested these physical parameters, along with the near‐infrared luminosities of the stars, against stellar evolution models for low‐mass stars. Discrepancies between the measured and theoretical values point toward a low‐level departure from the predictions. These results are among the most precise masses measured for visual binaries

Reducing the Clinical and Public Health Burden of Familial Hypercholesterolemia A Global Call to Action

Q1Q1Artículo completoE1-E13IMPORTANCE Familial hypercholesterolemia (FH) is an underdiagnosed and undertreated genetic disorder that leads to premature morbidity and mortality due to atherosclerotic cardiovascular disease. Familial hypercholesterolemia affects 1 in 200 to 250 people around the world of every race and ethnicity. The lack of general awareness of FH among the public and medical community has resulted in only 10% of the FH population being diagnosed and adequately treated. The World Health Organization recognized FH as a public health priority in 1998 during a consultation meeting in Geneva, Switzerland. The World Health Organization report highlighted 11 recommendations to address FH worldwide, from diagnosis and treatment to family screening and education. Research since the 1998 report has increased understanding and awareness of FH, particularly in specialty areas, such as cardiology and lipidology. However, in the past 20 years, there has been little progress in implementing the 11 recommendations to prevent premature atherosclerotic cardiovascular disease in an entire generation of families with FH. OBSERVATIONS In 2018, the Familial Hypercholesterolemia Foundation and the World Heart Federation convened the international FH community to update the 11 recommendations. Two meetings were held: one at the 2018 FH Foundation Global Summit and the other during the 2018 World Congress of Cardiology and Cardiovascular Health. Each meeting served as a platform for the FH community to examine the original recommendations, assess the gaps, and provide commentary on the revised recommendations. The Global Call to Action on Familial Hypercholesterolemia thus represents individuals with FH, advocacy leaders, scientific experts, policy makers, and the original authors of the 1998 World Health Organization report. Attendees from 40 countries brought perspectives on FH from low-, middle-, and high-income regions. Tables listing country-specific government support for FH care, existing country-specific and international FH scientific statements and guidelines, country-specific and international FH registries, and known FH advocacy organizations around the world were created. CONCLUSIONS AND RELEVANCE By adopting the 9 updated public policy recommendations created for this document, covering awareness; advocacy; screening, testing, and diagnosis; treatment; family-based care; registries; research; and cost and value, individual countries have the opportunity to prevent atherosclerotic heart disease in their citizens carrying a gene associated with FH and, likely, all those with severe hypercholesterolemia as well

The anti-tumor drug E7107 reveals an essential role for SF3b in remodeling U2 snRNP to expose the branch point-binding region

Duplex formation between the branch point-binding region (BBR) of U2 snRNA and the branch point sequence (BPS) in the intron is essential for splicing. Both the BBR and BPS interact with the U2 small nuclear ribonucleoprotein (snRNP)-associated SF3b complex, which is the target of the anti-tumor drug E7107. We show that E7107 blocks spliceosome assembly by preventing tight binding of U2 snRNP to pre-mRNA. E7107 has no apparent effect on U2 snRNP integrity. Instead, E7107 abolishes an ATP-dependent conformational change in U2 snRNP that exposes the BBR. We conclude that SF3b is required for this remodeling, which exposes the BBR for tight U2 snRNP binding to pre-mRNA

RNAi of ZC11A causes retention of polyA+ RNA in the nucleoplasm.

<p>A, B. The knockdown efficiency of ZC11A (A) or UAP56 (B) in HeLa cells was analyzed by Western. Loading controls were eIF4A3 (A) and CBP80 (B). Non-targeting siRNA was used as a control (cntl). C. Knockdown of ZC11A or UAP56/DDX39A results in retention of polyA+ RNA in the nucleus. PolyA+ RNA was visualized by FISH using an Alexa Fluor labeled oligo dT(70) probe. Scale bar, 10 µm. D. Same as C, except showing higher magnification of FISH images. Scale bar, 10 µm.</p

PDIP3 and ZC11A associate with the TREX complex.

<p>A, B. An antibody against PDIP3 (A) or ZC11A (B) recognizes their respective antigens on a Western blot, and IPs them from nuclear extract. We note that in the input lane ZC11A antibodies detect another band (designated by +), which may be non-specific. 10% of the input was loaded for the IPs. C, D, E. Nuclear extract was RNase-treated (C) and IPs were carried out with the indicated antibodies (D, E) incubated in the presence of ATP. Antibodies against the indicated proteins were used for Westerns. The bands designated by the asterisks are heavy and light chains of the antibody.</p

PDIP3 and ZC11A associate with UAP56 and the TREX complex in an ATP-dependent manner.

<p>A, B. IPs were carried out with the indicated antibodies using RNase-treated nuclear extract incubated in the presence or absence of ATP. Antibodies against the indicated proteins were used for Westerns.</p