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Clodagh c o'shea

Job Dekker, Andrew S Belmont, Mitchell Guttman, Victor O Leshyk, John T Lis, Stavros Lomvardas, Leonid A Mirny, Clodagh C O'Shea, Peter J Park, Bing Ren, Joan C Ritland Politz, Jay Shendure, Sheng Zhong
This corrects the article DOI: 10.1038/nature23884.
December 14, 2017: Nature
Job Dekker, Andrew S Belmont, Mitchell Guttman, Victor O Leshyk, John T Lis, Stavros Lomvardas, Leonid A Mirny, Clodagh C O'Shea, Peter J Park, Bing Ren, Joan C Ritland Politz, Jay Shendure, Sheng Zhong
The 4D Nucleome Network aims to develop and apply approaches to map the structure and dynamics of the human and mouse genomes in space and time with the goal of gaining deeper mechanistic insights into how the nucleus is organized and functions. The project will develop and benchmark experimental and computational approaches for measuring genome conformation and nuclear organization, and investigate how these contribute to gene regulation and other genome functions. Validated experimental technologies will be combined with biophysical approaches to generate quantitative models of spatial genome organization in different biological states, both in cell populations and in single cells...
September 13, 2017: Nature
Horng D Ou, Sébastien Phan, Thomas J Deerinck, Andrea Thor, Mark H Ellisman, Clodagh C O'Shea
The chromatin structure of DNA determines genome compaction and activity in the nucleus. On the basis of in vitro structures and electron microscopy (EM) studies, the hierarchical model is that 11-nanometer DNA-nucleosome polymers fold into 30- and subsequently into 120- and 300- to 700-nanometer fibers and mitotic chromosomes. To visualize chromatin in situ, we identified a fluorescent dye that stains DNA with an osmiophilic polymer and selectively enhances its contrast in EM. Using ChromEMT (ChromEM tomography), we reveal the ultrastructure and three-dimensional (3D) organization of individual chromatin polymers, megabase domains, and mitotic chromosomes...
July 28, 2017: Science
Yusuf Tufail, Daniela Cook, Lawrence Fourgeaud, Colin J Powers, Katharina Merten, Charles L Clark, Elizabeth Hoffman, Alexander Ngo, Kohei J Sekiguchi, Clodagh C O'Shea, Greg Lemke, Axel Nimmerjahn
Microglia are the intrinsic immune sentinels of the central nervous system. Their activation restricts tissue injury and pathogen spread, but in some settings, including viral infection, this response can contribute to cell death and disease. Identifying mechanisms that control microglial responses is therefore an important objective. Using replication-incompetent adenovirus 5 (Ad5)-based vectors as a model, we investigated the mechanisms through which microglia recognize and respond to viral uptake. Transgenic, immunohistochemical, molecular-genetic, and fluorescence imaging approaches revealed that phosphatidylserine (PtdSer) exposure on the outer leaflet of transduced cells triggers their engulfment by microglia through TAM receptor-dependent mechanisms...
February 8, 2017: Neuron
Horng D Ou, Thomas J Deerinck, Eric Bushong, Mark H Ellisman, Clodagh C O'Shea
No abstract text is available yet for this article.
May 21, 2016: Methods: a Companion to Methods in Enzymology
Govind A Shah, Clodagh C O'Shea
In response to cellular genome breaks, MRE11/RAD50/NBS1 (MRN) activates a global ATM DNA damage response (DDR) that prevents cellular replication. Here, we show that MRN-ATM also has critical functions in defending the cell against DNA viruses. We reveal temporally distinct responses to adenovirus genomes: a critical MRN-ATM DDR that must be inactivated by E1B-55K/E4-ORF3 viral oncoproteins and a global MRN-independent ATM DDR to viral nuclear domains that does not impact viral replication. We show that MRN binds to adenovirus genomes and activates a localized ATM response that specifically prevents viral DNA replication...
August 27, 2015: Cell
Jennifer M Higginbotham, Clodagh C O'Shea
UNLABELLED: Adenovirus E4-ORF3 and E1B-55K converge in subverting critical overlapping cellular pathways to facilitate virus replication. Here, we show that E1B-55K and E4-ORF3 induce sumoylation and the assembly of SUMO2/3 viral genome replication domains. Using a conjugation-deficient SUMO2 construct, we demonstrate that SUMO2/3 is recruited to E2A viral genome replication domains through noncovalent interactions. E1B-55K and E4-ORF3 have critical functions in inactivating MRN and ATM to facilitate viral genome replication...
October 2015: Journal of Virology
Thomas Heimbucher, Zheng Liu, Carine Bossard, Richard McCloskey, Andrea C Carrano, Christian G Riedel, Bogdan Tanasa, Christian Klammt, Bryan R Fonslow, Celine E Riera, Bjorn F Lillemeier, Kenneth Kemphues, John R Yates, Clodagh O'Shea, Tony Hunter, Andrew Dillin
FOXO family transcription factors are downstream effectors of Insulin/IGF-1 signaling (IIS) and major determinants of aging in organisms ranging from worms to man. The molecular mechanisms that actively promote DAF16/FOXO stability and function are unknown. Here we identify the deubiquitylating enzyme MATH-33 as an essential DAF-16 regulator in IIS, which stabilizes active DAF-16 protein levels and, as a consequence, influences DAF-16 functions, such as metabolism, stress response, and longevity in C. elegans...
July 7, 2015: Cell Metabolism
Horng D Ou, Thomas J Deerinck, Eric Bushong, Mark H Ellisman, Clodagh C O'Shea
Structural studies of viral proteins most often use high-resolution techniques such as X-ray crystallography, nuclear magnetic resonance, single particle negative stain, or cryo-electron microscopy (EM) to reveal atomic interactions of soluble, homogeneous viral proteins or viral protein complexes. Once viral proteins or complexes are separated from their host's cellular environment, their natural in situ structure and details of how they interact with other cellular components may be lost. EM has been an invaluable tool in virology since its introduction in the late 1940's and subsequent application to cells in the 1950's...
November 15, 2015: Methods: a Companion to Methods in Enzymology
Shigeki J Miyake-Stoner, Clodagh C O'Shea
Viral and cellular oncogenes converge in targeting critical protein interaction networks to reprogram the cellular DNA and protein replication machinery for pathological replication. In this issue, Thai et al. (2014) show that adenovirus E4ORF1 activates MYC glycolytic targets to induce a Warburg-like effect that converts glucose into nucleotides for viral replication.
April 1, 2014: Cell Metabolism
Horng D Ou, Witek Kwiatkowski, Thomas J Deerinck, Andrew Noske, Katie Y Blain, Hannah S Land, Conrado Soria, Colin J Powers, Andrew P May, Xiaokun Shu, Roger Y Tsien, James A J Fitzpatrick, Jeff A Long, Mark H Ellisman, Senyon Choe, Clodagh C O'Shea
Evolution of minimal DNA tumor virus' genomes has selected for small viral oncoproteins that hijack critical cellular protein interaction networks. The structural basis for the multiple and dominant functions of adenovirus oncoproteins has remained elusive. E4-ORF3 forms a nuclear polymer and simultaneously inactivates p53, PML, TRIM24, and MRE11/RAD50/NBS1 (MRN) tumor suppressors. We identify oligomerization mutants and solve the crystal structure of E4-ORF3. E4-ORF3 forms a dimer with a central β core, and its structure is unrelated to known polymers or oncogenes...
October 12, 2012: Cell
Horng D Ou, Andrew P May, Clodagh C O'Shea
One of the greatest challenges in biomedicine is to define the critical targets and network interactions that are subverted to elicit growth deregulation in human cells. Understanding and developing rational treatments for cancer requires a definition of the key molecular targets and how they interact to elicit the complex growth deregulation phenotype. Viral proteins provide discerning and powerful probes to understand both how cells work and how they can be manipulated using a minimal number of components...
January 2011: Wiley Interdisciplinary Reviews. Systems Biology and Medicine
Kristen C Espantman, Clodagh C O'Shea
The MAGE proteins are best known as curious tumor-specific antigens. However, Doyle et al. (2010) reveal that MAGE proteins interact with RING proteins to promote ubiquitylation which provides important new insights into the physiological and pathological functions of this enigmatic family of proteins.
September 24, 2010: Molecular Cell
Conrado Soria, Fanny E Estermann, Kristen C Espantman, Clodagh C O'Shea
The transcription factor p53 (also known as TP53) guards against tumour and virus replication and is inactivated in almost all cancers. p53-activated transcription of target genes is thought to be synonymous with the stabilization of p53 in response to oncogenes and DNA damage. During adenovirus replication, the degradation of p53 by E1B-55k is considered essential for p53 inactivation, and is the basis for p53-selective viral cancer therapies. Here we reveal a dominant epigenetic mechanism that silences p53-activated transcription, irrespective of p53 phosphorylation and stabilization...
August 26, 2010: Nature
Demetris C Iacovides, Clodagh C O'Shea, Juan Oses-Prieto, Alma Burlingame, Frank McCormick
During the late stages of adenovirus infection, the 100K protein (100K) inhibits the translation of cellular messages in the cytoplasm and regulates hexon trimerization and assembly in the nucleus. However, it is not known how it switches between these two functions. Here we show that 100K is methylated on arginine residues at its C terminus during infection and that this region is necessary for binding PRMT1 methylase. Methylated 100K is exclusively nuclear. Mutation of the third RGG motif (amino acids 741 to 743) prevents localization to the nucleus during infection, suggesting that methylation of that sequence is important for 100K shuttling...
December 2007: Journal of Virology
Ingo Ringshausen, Clodagh C O'Shea, Andrew J Finch, Lamorna Brown Swigart, Gerard I Evan
There is currently much interest in the idea of restoring p53 activity in tumor cells by inhibiting Hdm2/Mdm2. However, it has remained unclear whether this would also activate p53 in normal cells. Using a switchable endogenous p53 mouse model, which allows rapid and reversible toggling of p53 status between wild-type and null states, we show that p53 is spontaneously active in all tested tissues of mdm2-deficient mice, triggering fatal pathologies that include ablation of classically radiosensitive tissues...
December 2006: Cancer Cell
Clodagh C O'Shea
DNA viruses have enormous utility in cancer research, both as tools for tumor target discovery as well as agents for lytic cancer therapies. This is because there is a profound functional overlap between the DNA viral and tumor cell programs. DNA viruses encode proteins that elicit growth deregulation in infected cells similar to that engendered by mutations in tumor cells. Evolution has refined viral proteins to target the critical cellular hubs that regulate growth. Thus, viral proteins are discriminating biochemical probes that can be used to identify and characterize novel tumor targets...
November 21, 2005: Oncogene
Clodagh C O'Shea
No abstract text is available yet for this article.
November 21, 2005: Oncogene
Clodagh C O'Shea, Conrado Soria, Bridget Bagus, Frank McCormick
ONYX-015 is an E1B-55K-deleted adenovirus that has promising clinical activity as a cancer therapy. However, many tumor cells fail to support ONYX-015 oncolytic replication. E1B-55K functions include p53 degradation, RNA export, and host protein shutoff. Here, we show that resistant tumor cell lines fail to provide the RNA export functions of E1B-55K necessary for ONYX-015 replication; viral 100K mRNA export is necessary for host protein shutoff. However, heat shock rescues late viral RNA export and renders refractory tumor cells permissive to ONYX-015...
July 2005: Cancer Cell
Clodagh C O'Shea, Serah Choi, Frank McCormick, David Stokoe
mTOR is a critical regulator of protein translation, and plays an important role in controlling cellular replication. Recent studies indicate that nutrient and growth factor mediated activation of mTOR is deregulated in human cancer, and therefore represents an attractive tumor target. However, activation of mTOR is a complex process that is not yet fully understood. DNA viruses and tumor cells often perturb similar cellular pathways to facilitate their replication. In a recent study, we used adenovirus as a novel tool to probe the mechanisms underlying the inappropriate activation of mTOR upon virus infection of quiescent primary cells...
July 2005: Cell Cycle
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