Genomic Exploration of the Hemiascomycetous Yeasts: 1. A set of yeast species for molecular evolution studies11Sequences and annotations are accessible at: Génoscope (http://www.genoscope.cns.fr), FEBS Letters Website (http://www.elsevier.nl/febs/show/), Bordeaux (http://cbi.genopole-bordeaux.fr/Genolevures) and were deposited into the EMBL database (accession number from AL392203 to AL441602).

AbstractThe identification of molecular evolutionary mechanisms in eukaryotes is approached by a comparative genomics study of a homogeneous group of species classified as Hemiascomycetes. This group includes Saccharomyces cerevisiae, the first eukaryotic genome entirely sequenced, back in 1996. A random sequencing analysis has been performed on 13 different species sharing a small genome size and a low frequency of introns. Detailed information is provided in the 20 following papers. Additional tables available on websites describe the ca. 20 000 newly identified genes. This wealth of data, so far unique among eukaryotes, allowed us to examine the conservation of chromosome maps, to identify the ‘yeast-specific’ genes, and to review the distribution of gene families into functional classes. This project conducted by a network of seven French laboratories has been designated ‘Génolevures’

CDK4/6 inhibitor-mediated cell overgrowth triggers osmotic and replication stress to promote senescence

Summary. Abnormal increases in cell size are associated with senescence and cell cycle exit. The mechanisms by which overgrowth primes cells to withdraw from the cell cycle remain unknown. We address this question using CDK4/6 inhibitors, which arrest cells in G0/G1 and are licensed to treat advanced HR+/HER2− breast cancer. We demonstrate that CDK4/6-inhibited cells overgrow during G0/G1, causing p38/p53/p21-dependent cell cycle withdrawal. Cell cycle withdrawal is triggered by biphasic p21 induction. The first p21 wave is caused by osmotic stress, leading to p38- and size-dependent accumulation of p21. CDK4/6 inhibitor washout results in some cells entering S-phase. Overgrown cells experience replication stress, resulting in a second p21 wave that promotes cell cycle withdrawal from G2 or the subsequent G1. We propose that the levels of p21 integrate signals from overgrowth-triggered stresses to determine cell fate. This model explains how hypertrophy can drive senescence and why CDK4/6 inhibitors have long-lasting effects in patients

14-3-3ζ Interacts with Stat3 and Regulates Its Constitutive Activation in Multiple Myeloma Cells

The 14-3-3 proteins are a family of regulatory signaling molecules that interact with other proteins in a phosphorylation-dependent manner and function as adapter or scaffold proteins in signal transduction pathways. One family member, 14-3-3ζ, is believed to function in cell signaling, cycle control, and apoptotic death. A systematic proteomic analysis done in our laboratory has identified signal transducers and activators of transcription 3 (Stat3) as a novel 14-3-3ζ interacting protein. Following our initial finding, in this study, we provide evidence that 14-3-3ζ interacts physically with Stat3. We further demonstrate that phosphorylation of Stat3 at Ser727 is vital for 14-3-3ζ interaction and mutation of Ser727 to Alanine abolished 14-3-3ζ/Stat3 association. Inhibition of 14-3-3ζ protein expression in U266 cells inhibited Stat3 Ser727 phosphorylation and nuclear translocation, and decreased both Stat3 DNA binding and transcriptional activity. Moreover, 14-3-3ζ is involved in the regulation of protein kinase C (PKC) activity and 14-3-3ζ binding to Stat3 protects Ser727 dephosphorylation from protein phosphatase 2A (PP2A). Taken together, our findings support the model that multiple signaling events impinge on Stat3 and that 14-3-3ζ serves as an essential coordinator for different pathways to regulate Stat3 activation and function in MM cells

Genomic Exploration of the Hemiascomycetous Yeasts: 19. Ascomycetes-specific genes

AbstractComparisons of the 6213 predicted Saccharomyces cerevisiae open reading frame (ORF) products with sequences from organisms of other biological phyla differentiate genes commonly conserved in evolution from ‘maverick’ genes which have no homologue in phyla other than the Ascomycetes. We show that a majority of the ‘maverick’ genes have homologues among other yeast species and thus define a set of 1892 genes that, from sequence comparisons, appear ‘Ascomycetes-specific’. We estimate, retrospectively, that the S. cerevisiae genome contains 5651 actual protein-coding genes, 50 of which were identified for the first time in this work, and that the present public databases contain 612 predicted ORFs that are not real genes. Interestingly, the sequences of the ‘Ascomycetes-specific’ genes tend to diverge more rapidly in evolution than that of other genes. Half of the ‘Ascomycetes-specific’ genes are functionally characterized in S. cerevisiae, and a few functional categories are over-represented in them

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Etude de la sélection naturelle dans les populations de faible effectif : le cas de la drépanocytose chez les Bedik et les Malinké de la région de Kégoudou (Sénégal oriental)

Natural selection study in small size populations. The drepanocytosis case in Madinka and Bedik from the Kedougou region (Eastern Senegal). — We undertook to study the effects of natural selection deriving from the mutation of haemoglobin A into haemoglobin S among a Madenka population in Niokholo (Eastern Senegal). The genealogical data bear on 1172 individuals. We got a blood sample from 596 of them. There are no SS homozygotes, and the AA heterozygote ratio is 19 %. The study of distribution by age, of female fertility, of survival during the first years reveals no significant difference between the AA and AS groups. This study goes on with the analysis of 331 parent-child pairs in this very population, and of 256 mother-child pairs taken among the Bedik, a neighbouring population for which the hétérozygote ratio is 28 %. Once again we were not able to find any differential selection for the AS genotype. And so we focussed on the power of the test we used. We showed that the test is not powerful enough to reveal a differential selection even though the hétérozygote ratio is rather high. This is due to the small size of the observed samples.Dans une population de Madenka du Niokholo (Sénégal Oriental) nous avons entrepris d'étudier les effets de la sélection naturelle provenant de la mutation de l'hémoglobine A en hémoglobine S. Les données généalogiques portent sur 1 172 individus. 596 d'entre eux ont subi une prise de sang. Il n'y a pas d'homozygote SS, le taux d'hétérozygotes AS est de 19 %. L'étude de la répartition par âge, de la fécondité des femmes, de la survie aux premiers âges selon le génotype ne montre pas de différence significative entre les individus AA et AS. L'étude a été poursuivie par l'analyse de 331 couples parent-enfant dans cette population et 256 couples mère-enfant chez les Bedik, une population voisine ou le taux d'hétérozygotes s'élève à 28 %. Là encore nous n'avons pu mettre en évidence une différentielle de sélection pour ce gène. Nous nous sommes alors penché sur la puissance du test utilisé. Nous avons montré que le test n'est pas suffisamment puissant pour mettre en évidence une différentielle de sélecon du fait de la petite taille des échantillons observés, malgré des taux relativement élevés d'hétérozygotes.Saurin William. Etude de la sélection naturelle dans les populations de faible effectif : le cas de la drépanocytose chez les Bedik et les Malinké de la région de Kégoudou (Sénégal oriental). In: Bulletins et Mémoires de la Société d'anthropologie de Paris, XIV° Série. Tome 1 fascicule 1, 1984. pp. 37-56

Estimation of electric field effects on the adsorption of molecular superoxide species on Au based on density functional theory

Superoxide species are key intermediates in the oxygen reduction reactions (ORR) that occur at the cathodes of aprotic metal-air batteries. Herein we report a DFT study of the effects of an externally applied electric field (ε) on the stability of various molecular superoxide species, including MO (M = Li, Na, K) and O, on gold surfaces, which shows that the stability of such species on Au electrodes can be materially affected by the presence of an electric field and solvent molecules, suggesting that such effects should be included in the first-principles modeling of cathode reactions in metal-O cells. In the ε range of ±0.4 V Å, the stability of MO species is found to vary by up to |0.4| eV on Au(111) and |0.2| eV on Au(211) in vacuo, which is larger than the field effects on the stability of O and OH, key intermediates in the ORR by hydrogen. An aprotic solvent such as dimethyl sulfoxide (DMSO), considered here via the inclusion of explicit DMSO molecules above the Au surfaces, stabilizes all three MO species at zero fields and amplifies the field effects on the stability of MO, on both Au surfaces. The variations in the stability of the molecular MO species with ε, which have small polarizabilities, are closely approximated by the first-order Stark effect (μ·ε, where μ is the static surface dipole moment induced by adsorption at ε = 0 V Å). The superoxide anion (O) that has been identified on an under-coordinated Au site has a larger polarizability than the MO species and a μ that is opposite in sign to those of the metal MO species, which results in larger errors by the first-order approximation, although its stability varies only moderately under positive electric fields of up to 0.4 V Å

Location of tolerated insertions/deletions in the structure of the maltose binding protein

AbstractIn a previous study [(1987) J. Mol. Biol. 194, 663-673], we isolated ten insertion/deletion mutants (indels) of the maltose binding protein for which the maltose binding constant was only a little or not at all affected. In this paper, we have localized these mutations in the recently solved three-dimensional structure. Contrary to the general expectation, most of the insertion/deletion modifications occurred within elements of secondary structure. An analysis of the inserted residues for three indels found within α helices allowed an interpretation regarding protein structure accommodation to such modifications