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Dynamics of PARKIN-Dependent Mitochondrial Ubiquitylation in Induced Neurons and Model Systems Revealed by Digital Snapshot Proteomics.

Related Articles

Dynamics of PARKIN-Dependent Mitochondrial Ubiquitylation in Induced Neurons and Model Systems Revealed by Digital Snapshot Proteomics.

Mol Cell. 2018 Apr 11;:

Authors: Ordureau A, Paulo JA, Zhang W, Ahfeldt T, Zhang J, Cohn EF, Hou Z, Heo JM, Rubin LL, Sidhu SS, Gygi SP, Harper JW

Abstract
Flux through kinase and ubiquitin-driven signaling systems depends on the modification kinetics, stoichiometry, primary site specificity, and target abundance within the pathway, yet we rarely understand these parameters and their spatial organization within cells. Here we develop temporal digital snapshots of ubiquitin signaling on the mitochondrial outer membrane in embryonic stem cell-derived neurons, and we model HeLa cell systems upon activation of the PINK1 kinase and PARKIN ubiquitin ligase by proteomic counting of ubiquitylation and phosphorylation events. We define the kinetics and site specificity of PARKIN-dependent target ubiquitylation, and we demonstrate the power of this approach to quantify pathway modulators and to mechanistically define the role of PARKIN UBL phosphorylation in pathway activation in induced neurons. Finally, through modulation of pS65-Ub on mitochondria, we demonstrate that Ub hyper-phosphorylation is inhibitory to mitophagy receptor recruitment, indicating that pS65-Ub stoichiometry in vivo is optimized to coordinate PARKIN recruitment via pS65-Ub and mitophagy receptors via unphosphorylated chains.

PMID: 29656925 [PubMed - as supplied by publisher]



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Inference of the Human Polyadenylation Code.

Inference of the Human Polyadenylation Code.

Bioinformatics. 2018 Apr 10;:

Authors: Leung MKK, Delong A, Frey BJ

Abstract
Motivation: Processing of transcripts at the 3'-end involves cleavage at a polyadenylation site followed by the addition of a poly(A)-tail. By selecting which site is cleaved, the process of alternative polyadenylation enables genes to produce transcript isoforms with different 3'-ends. To facilitate the identification and treatment of disease-causing mutations that affect polyadenylation and to understand the sequence determinants underlying this regulatory process, a computational model that can accurately predict polyadenylation patterns from genomic features is desirable.
Results: Previous works have focused on identifying candidate polyadenylation sites and classifying tissue-specific sites. By training on how multiple sites in genes are competitively selected for polyadenylation from 3'-end sequencing data, we developed a deep learning model that can predict the tissue-specific strength of a polyadenylation site in the 3' untranslated region of the human genome given only its genomic sequence. We demonstrate the model's broad utility on multiple tasks, without any application-specific training. The model can be used to predict which polyadenylation site is more likely to be selected in genes with multiple sites. It can be used to scan the 3' untranslated region to find candidate polyadenylation sites. It can be used to classify the pathogenicity of variants near annotated polyadenylation sites in ClinVar. It can also be used to anticipate the effect of antisense oligonucleotide experiments to redirect polyadenylation. We provide analysis on how different features affect the model's predictive performance and a method to identify sensitive regions of the genome at the single-based resolution that can affect polyadenylation regulation.
Contact: frey@psi.toronto.edu.
Supplementary information: Supplementary data are available at Bioinformatics online.

PMID: 29648582 [PubMed - as supplied by publisher]



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Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma.

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Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma.

N Engl J Med. 2018 04 12;378(15):1396-1407

Authors: Schmitz R, Wright GW, Huang DW, Johnson CA, Phelan JD, Wang JQ, Roulland S, Kasbekar M, Young RM, Shaffer AL, Hodson DJ, Xiao W, Yu X, Yang Y, Zhao H, Xu W, Liu X, Zhou B, Du W, Chan WC, Jaffe ES, Gascoyne RD, Connors JM, Campo E, Lopez-Guillermo A, Rosenwald A, Ott G, Delabie J, Rimsza LM, Tay Kuang Wei K, Zelenetz AD, Leonard JP, Bartlett NL, Tran B, Shetty J, Zhao Y, Soppet DR, Pittaluga S, Wilson WH, Staudt LM

Abstract
BACKGROUND: Diffuse large B-cell lymphomas (DLBCLs) are phenotypically and genetically heterogeneous. Gene-expression profiling has identified subgroups of DLBCL (activated B-cell-like [ABC], germinal-center B-cell-like [GCB], and unclassified) according to cell of origin that are associated with a differential response to chemotherapy and targeted agents. We sought to extend these findings by identifying genetic subtypes of DLBCL based on shared genomic abnormalities and to uncover therapeutic vulnerabilities based on tumor genetics.
METHODS: We studied 574 DLBCL biopsy samples using exome and transcriptome sequencing, array-based DNA copy-number analysis, and targeted amplicon resequencing of 372 genes to identify genes with recurrent aberrations. We developed and implemented an algorithm to discover genetic subtypes based on the co-occurrence of genetic alterations.
RESULTS: We identified four prominent genetic subtypes in DLBCL, termed MCD (based on the co-occurrence of MYD88L265P and CD79B mutations), BN2 (based on BCL6 fusions and NOTCH2 mutations), N1 (based on NOTCH1 mutations), and EZB (based on EZH2 mutations and BCL2 translocations). Genetic aberrations in multiple genes distinguished each genetic subtype from other DLBCLs. These subtypes differed phenotypically, as judged by differences in gene-expression signatures and responses to immunochemotherapy, with favorable survival in the BN2 and EZB subtypes and inferior outcomes in the MCD and N1 subtypes. Analysis of genetic pathways suggested that MCD and BN2 DLBCLs rely on "chronic active" B-cell receptor signaling that is amenable to therapeutic inhibition.
CONCLUSIONS: We uncovered genetic subtypes of DLBCL with distinct genotypic, epigenetic, and clinical characteristics, providing a potential nosology for precision-medicine strategies in DLBCL. (Funded by the Intramural Research Program of the National Institutes of Health and others.).

PMID: 29641966 [PubMed - indexed for MEDLINE]



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Orchestrating Ribosomal Subunit Coordination to Control Stem Cell Fate.

Orchestrating Ribosomal Subunit Coordination to Control Stem Cell Fate.

Cell Stem Cell. 2018 Apr 05;22(4):471-473

Authors: Sharma E, Blencowe BJ

Abstract
The mechanisms responsible for maintaining ribosomal component stoichiometry, which is critical during cell fate transitions, are currently not well understood. In this issue of Cell Stem Cell, Corsini et al. (2018) demonstrate that the transcription and splicing-associated factor HTATSF1 controls stem cell fate by coordinately regulating ribosomal protein and RNA production.

PMID: 29625061 [PubMed - in process]



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An incoherent feedforward loop facilitates adaptive tuning of gene expression.

An incoherent feedforward loop facilitates adaptive tuning of gene expression.

Elife. 2018 Apr 05;7:

Authors: Hong J, Brandt N, Abdual-Rahman F, Yang AWH, Hughes TR, Gresham D

Abstract
We studied adaptive evolution of gene expression using long-term experimental evolution of Saccharomyces cerevisiae in ammonium-limited chemostats. We found repeated selection for non-synonymous variation in the DNA binding domain of the transcriptional activator, GAT1, which functions with the repressor, DAL80 in an incoherent type-1 feedforward loop (I1-FFL) to control expression of the high affinity ammonium transporter gene, MEP2. Missense mutations in the DNA binding domain of GAT1 reduce its binding to the GATAA consensus sequence. However, we show experimentally, and using mathematical modeling, that decreases in GAT1 binding result in increased expression of MEP2 as a consequence of properties of I1-FFLs. Our results show that I1-FFLs, one of the most commonly occurring network motifs in transcriptional networks, can facilitate adaptive tuning of gene expression through modulation of transcription factor binding affinities. Our findings highlight the importance of gene regulatory architectures in the evolution of gene expression.

PMID: 29620523 [PubMed - as supplied by publisher]



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Integrating images from multiple microscopy screens reveals diverse patterns of protein subcellular localization change.

Integrating images from multiple microscopy screens reveals diverse patterns of protein subcellular localization change.

Elife. 2018 Apr 05;7:

Authors: Lu AX, Chong YT, Hsu IS, Strome B, Handfield LF, Kraus O, Andrews BJ, Moses AM

Abstract
Evaluating protein localization changes on a systematic level is a powerful tool for understanding how cells respond to environmental, chemical, or genetic perturbations. To date, work in understanding these proteomic responses through high-throughput imaging has catalogued localization changes independently for each perturbation. To distinguish changes that are targeted responses to the specific perturbation and more generalized programs, we developed a scalable approach to visualize the localization behavior of proteins across multiple experiments as a quantitative pattern. By applying this approach to 24 experimental screens consisting of nearly 400,000 images, we differentiate specific responses from more generalized ones, discover nuance in the localization behavior of stress-responsive proteins, and form hypotheses by clustering proteins with similar patterns. While previous approaches aim to capture all localization changes for a single screen as accurately as possible, our work aims to integrate large amounts of imaging data to find unexpected new cell biology.

PMID: 29620521 [PubMed - as supplied by publisher]



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Identification of CDC25 as a Common Therapeutic Target for Triple-Negative Breast Cancer.

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Identification of CDC25 as a Common Therapeutic Target for Triple-Negative Breast Cancer.

Cell Rep. 2018 Apr 03;23(1):112-126

Authors: Liu JC, Granieri L, Shrestha M, Wang DY, Vorobieva I, Rubie EA, Jones R, Ju Y, Pellecchia G, Jiang Z, Palmerini CA, Ben-David Y, Egan SE, Woodgett JR, Bader GD, Datti A, Zacksenhaus E

Abstract
CDK4/6 inhibitors are effective against cancer cells expressing the tumor suppressor RB1, but not RB1-deficient cells, posing the challenge of how to target RB1 loss. In triple-negative breast cancer (TNBC), RB1 and PTEN are frequently inactivated together with TP53. We performed kinome/phosphatase inhibitor screens on primary mouse Rb/p53-, Pten/p53-, and human RB1/PTEN/TP53-deficient TNBC cell lines and identified CDC25 phosphatase as a common target. Pharmacological or genetic inhibition of CDC25 suppressed growth of RB1-deficient TNBC cells that are resistant to combined CDK4/6 plus CDK2 inhibition. Minimal cooperation was observed in vitro between CDC25 antagonists and CDK1, CDK2, or CDK4/6 inhibitors, but strong synergy with WEE1 inhibition was apparent. In accordance with increased PI3K signaling following long-term CDC25 inhibition, CDC25 and PI3K inhibitors effectively synergized to suppress TNBC growth both in vitro and in xenotransplantation models. These results provide a rationale for the development of CDC25-based therapies for diverse RB1/PTEN/TP53-deficient and -proficient TNBCs.

PMID: 29617654 [PubMed - in process]



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Automated Computational Inference of Multi-protein Assemblies from Biochemical Co-purification Data.

Automated Computational Inference of Multi-protein Assemblies from Biochemical Co-purification Data.

Methods Mol Biol. 2018;1764:391-399

Authors: Goebels F, Hu L, Bader G, Emili A

Abstract
Biology has amassed a wealth of information about the function of a multitude of protein-coding genes across species. The challenge now is to understand how all these proteins work together to form a living organism, and a crucial step for gaining this knowledge is a complete description of the molecular "wiring circuits" that underlie cellular processes. In this chapter, we describe a general computational framework for predicting multi-protein assemblies from biochemical co-fractionation data.

PMID: 29605929 [PubMed - in process]



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Global Characterization of Protein Complexes by Biochemical Purification-Mass Spectrometry (BP/MS).

Global Characterization of Protein Complexes by Biochemical Purification-Mass Spectrometry (BP/MS).

Methods Mol Biol. 2018;1764:185-191

Authors: Pourhaghighi R, Emili A

Abstract
A proteomic platform for global analysis of protein complexes and protein-protein interactions (PPIs) is described. Briefly, after comprehensive physiochemical separation of soluble protein extracts using non-denaturing ion exchange chromatography (IEX), each fraction is subjected to quantitative tandem mass spectrometry analysis.

PMID: 29605916 [PubMed - in process]



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Standardization of left atrial, right ventricular, and right atrial deformation imaging using two-dimensional speckle tracking echocardiography: a consensus document of the EACVI/ASE/Industry Task Force to standardize deformation imaging.

Standardization of left atrial, right ventricular, and right atrial deformation imaging using two-dimensional speckle tracking echocardiography: a consensus document of the EACVI/ASE/Industry Task Force to standardize deformation imaging.

Eur Heart J Cardiovasc Imaging. 2018 Mar 27;:

Authors: Badano LP, Kolias TJ, Muraru D, Abraham TP, Aurigemma G, Edvardsen T, D'Hooge J, Donal E, Fraser AG, Marwick T, Mertens L, Popescu BA, Sengupta PP, Lancellotti P, Thomas JD, Voigt JU, EACVI Scientific Documents Committee

Abstract
The EACVI/ASE/Industry Task Force to standardize deformation imaging prepared this consensus document to standardize definitions and techniques for using two-dimensional (2D) speckle tracking echocardiography (STE) to assess left atrial, right ventricular, and right atrial myocardial deformation. This document is intended for both the technical engineering community and the clinical community at large to provide guidance on selecting the functional parameters to measure and how to measure them using 2D STE.This document aims to represent a significant step forward in the collaboration between the scientific societies and the industry since technical specifications of the software packages designed to post-process echocardiographic datasets have been agreed and shared before their actual development. Hopefully, this will lead to more clinically oriented software packages which will be better tailored to clinical needs and will allow industry to save time and resources in their development.

PMID: 29596561 [PubMed - as supplied by publisher]



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