Recent publications
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Mon Oct 15, 2018 CIG Sem. B. Davidson

CIG Seminars Fall 2018

Monday 12:15, Génopode, auditorium A, followed by an apéro

Download the poster

Monday October 15, 2018 at 16h15
Beverly Davidson, The Children’s Hospital of Philadelphia, USA
«Emerging therapies for neurological diseases»
Host: Vincent Dion

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Cover of Nucleic Acids Research: group Stasiak

Link to the publication: http://www.genomyx.ch/nucleic-acids-res-auth-a-stasiak-2/ 

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J Biol Chem.: auth.: group Herr

 2018 Sep 17. pii: jbc.RA118.004185. doi: 10.1074/jbc.RA118.004185. [Epub ahead of print]

The conserved threonine-rich region of the HCF-1PRO repeat activates promiscuous OGT:UDP-GlcNAc glycosylation and proteolysis activities.

Abstract

O-linked N-acetylglucosamine transferase (OGT) possesses dual glycosyltransferase-protease activities. OGT thereby stably glycosylates serines and threonines of numerous proteins and, via a transient glutamate glycosylation, cleaves a single known substrate-the so-called HCF-1PRO repeat of the transcriptional co-regulator host-cell factor 1 (HCF-1). Here, we probed the relationship between these distinct glycosylation and proteolytic activities. For proteolysis, the HCF-1PRO repeat possesses an important extended threonine-rich region that is tightly bound by the OGT tetratricopeptide-repeat (TPR) region. We report that linkage of this HCF-1PRO-repeat, threonine-rich region to heterologous substrate sequences also potentiates robust serine glycosylation with the otherwise poor Rp-αS-UDP-GlcNAc diastereomer phosphorothioate and UDP-5S-GlcNAc OGT co-substrates. Furthermore, it potentiated proteolysis of a non-HCF-1PRO-repeat cleavage sequence, provided it contained an appropriately positioned glutamate residue. Using serine- or glutamate-containing HCF-1PRO-repeat sequences, we show that proposed OGT-based or UDP-GlcNAc-based serine-acceptor residue activation mechanisms can be circumvented independently, but not when disrupted together. In contrast, disruption of both proposed activation mechanisms even in combination did not inhibit OGT-mediated proteolysis. These results reveal a multiplicity of OGT glycosylation strategies, some leading to proteolysis, which could be targets of alternative molecular regulatory strategies.

KEYWORDS:

Host-cell factor-1; O-GlcNAcylation; O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT); enzyme mechanism; glycobiology; post-translational modification (PTM)

PMID: 30224358

 

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Mol Cell Oncol.: auth.: group Fajas

CDK4, a new metabolic sensor that antagonizes AMPK.

Abstract

Cyclin-dependent kinase 4 (CDK4) is a positive regulator of cell cycle progression, however, there is growing evidence demonstrating that its function exceeds the control of cell division. Here we show that CDK4 is an important regulator of cellular substrate utilization through direct inhibition of the metabolic regulator AMPK (AMP-activated protein kinase).

KEYWORDS:

AMPK; CDK4; Cell Cycle; Fatty acid oxidation; Metabolism; Tumor metabolism

PMID: 30263936

 

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Proc Natl Acad Sci U S A.: auth.: C.Fankhauser

 2018 Oct 1. pii: 201806084. doi: 10.1073/pnas.1806084115. [Epub ahead of print]

Changes in resource partitioning between and within organs support growth adjustment to neighbor proximity in Brassicaceae seedlings.

Abstract

In shade-intolerant plants, the perception of proximate neighbors rapidly induces architectural changes resulting in elongated stems and reduced leaf size. Sensing and signaling steps triggering this modified growth program have been identified. However, the underlying changes in resource allocation that fuel stem growth remain poorly understood. Through 14CO2 pulse labeling of Brassica rapa seedlings, we show that perception of the neighbor detection signal, low ratio of red to far-red light (R:FR), leads to increased carbon allocation from the major site of photosynthesis (cotyledons) to the elongating hypocotyl. While carbon fixation and metabolite levels remain similar in low R:FR, partitioning to all downstream carbon pools within the hypocotyl is increased. Genetic analyses using Arabidopsis thaliana mutants indicate that low-R:FR-induced hypocotyl elongation requires sucrose transport from the cotyledons and is regulated by a PIF7-dependent metabolic response. Moreover, our data suggest that starch metabolism in the hypocotyl has a growth-regulatory function. The results reveal a key mechanism by which metabolic adjustments can support rapid growth adaptation to a changing environment.

KEYWORDS:

PIF7; neighbor proximity detection; phytochrome B; resource partitioning; starch

PMID: 30275313

 

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Nucleic Acids Res.: co-auth.: I.Xenarios

 2018 Oct 1. doi: 10.1093/nar/gky876. [Epub ahead of print]

Updates in Rhea: SPARQLing biochemical reaction data.

Abstract

Rhea (http://www.rhea-db.org) is a comprehensive and non-redundant resource of over 11 000 expert-curated biochemical reactions that uses chemical entities from the ChEBI ontology to represent reaction participants. Originally designed as an annotation vocabulary for the UniProt Knowledgebase (UniProtKB), Rhea also provides reaction data for a range of other core knowledgebases and data repositories including ChEBI and MetaboLights. Here we describe recent developments in Rhea, focusing on a new resource description framework representation of Rhea reaction data and an SPARQL endpoint (https://sparql.rhea-db.org/sparql) that provides access to it. We demonstrate how federated queries that combine the Rhea SPARQL endpoint and other SPARQL endpoints such as that of UniProt can provide improved metabolite annotation and support integrative analyses that link the metabolome through the proteome to the transcriptome and genome. These developments will significantly boost the utility of Rhea as a means to link chemistry and biology for a more holistic understanding of biological systems and their function in health and disease.

PMID: 30272209