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1.
PLoS Pathog ; 16(10): e1008849, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-33002095

RESUMEN

Epstein-Barr virus (EBV) causes lymphomas and epithelial cell cancers. Though generally silent in B lymphocytes, this widely prevalent virus can cause endemic Burkitt lymphoma and post-transplant lymphoproliferative disorders/lymphomas in immunocompromised hosts. By learning how EBV breaches barriers to cell proliferation, we hope to undermine those strategies to treat EBV lymphomas and potentially other cancers. We had previously found that EBV, through activation of cellular STAT3 prevents phosphorylation of Chk1, and thereby, suppresses activation of the intra-S phase cell-cycle checkpoint, a potent barrier to oncogene-driven proliferation. This observation prompted us to examine the consequences on DNA repair since homologous recombination repair, the most error-free form, requires phosphoChk1. We now report that the defect in Chk1 phosphorylation also curtails RAD51 nucleation, and thereby, homologous recombination repair of DNA double strand breaks. The resulting reliance on error-prone microhomology-mediated end-joining (MMEJ) repair makes EBV-transformed cells susceptible to PARP inhibition and simultaneous accrual of genome-wide deletions and insertions resulting from synthesis-dependent MMEJ. Analysis of transcriptomic and drug susceptibility data from hundreds of cancer lines reveals a STAT3-dependent gene-set predictive of susceptibility of cancers to synthetic lethal PARP inhibition. These findings i) demonstrate how the tumor virus EBV re-shapes cellular DNA repair, ii) provide the first genome-wide evidence for insertions resulting from MMEJ in human cells, and iii) expand the range of cancers (EBV-related and -unrelated) that are likely to respond to synthetic lethal inhibitors given the high prevalence of cancers with constitutively active STAT3.


Asunto(s)
Linfocitos B/virología , Proteína BRCA1/metabolismo , Proteína BRCA2/metabolismo , Roturas del ADN de Doble Cadena , Infecciones por Virus de Epstein-Barr/virología , Reparación del ADN por Recombinación , Factor de Transcripción STAT3/metabolismo , Adolescente , Adulto , Linfocitos B/citología , Linfocitos B/metabolismo , Proteína BRCA1/genética , Proteína BRCA2/genética , Linfoma de Burkitt/genética , Linfoma de Burkitt/patología , Linfoma de Burkitt/virología , Proliferación Celular , Reparación del ADN por Unión de Extremidades , Infecciones por Virus de Epstein-Barr/genética , Infecciones por Virus de Epstein-Barr/metabolismo , Herpesvirus Humano 4/aislamiento & purificación , Humanos , Neoplasias/genética , Neoplasias/patología , Neoplasias/virología , Fosforilación , Factor de Transcripción STAT3/genética , Adulto Joven
2.
PLoS Pathog ; 15(12): e1008228, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31841561

RESUMEN

Epstein-Barr virus (EBV) is an oncogenic herpesvirus and WHO class 1 carcinogen that resides in B lymphocytes of nearly all humans. While silent in most, EBV can cause endemic Burkitt lymphoma in children and post-transplant lymphoproliferative disorders/lymphomas in immunocompromised hosts. The pathogenesis of such lymphomas is multifactorial but to a large extent depends on EBV's ability to aggressively drive cellular DNA replication and B cell proliferation despite cell-intrinsic barriers to replication. One such barrier is oncogenic replication stress which hinders the progression of DNA replication forks. To understand how EBV successfully overcomes replication stress, we examined cellular replication forks in EBV-transformed B cells using iPOND (isolation of Proteins on Nascent DNA)-mass spectrometry and identified several cellular proteins that had not previously been linked to DNA replication. Of eight candidate replisome-associated proteins that we validated at forks in EBV-transformed cells and Burkitt lymphoma-derived cells, three zinc finger proteins (ZFPs) were upregulated early in B cells newly-infected with EBV in culture as well as expressed at high levels in EBV-infected B blasts in the blood of immunocompromised transplant recipients. Expressed highly in S- and G2-phase cells, knockdown of each ZFP resulted in stalling of proliferating cells in the S-phase, cleavage of caspase 3, and cell death. These proteins, newly-identified at replication forks of EBV-transformed and Burkitt lymphoma cells therefore contribute to cell survival and cell cycle progression, and represent novel targets for intervention of EBV-lymphomas while simultaneously offering a window into how the replication machinery may be similarly modified in other cancers.


Asunto(s)
Linfocitos B/virología , Transformación Celular Viral/fisiología , Infecciones por Virus de Epstein-Barr/metabolismo , Origen de Réplica/fisiología , Dedos de Zinc/fisiología , Linfocitos B/patología , Linfoma de Burkitt/virología , Proliferación Celular/fisiología , Herpesvirus Humano 4 , Humanos
3.
Int J Mol Sci ; 19(8)2018 Jul 26.
Artículo en Inglés | MEDLINE | ID: mdl-30049932

RESUMEN

Under pro-inflammatory conditions, astrocytes become reactive and acquire a migratory phenotype. Our results show that hemichannels formed by connexin 43 (Cx43) play an important role in Thy-1-induced astrocyte migration. The neuronal protein Thy-1 binds to αvß3 integrin in astrocytes, thereby leading to intricate signaling pathways that include calcium (Ca2+) release from intracellular stores, opening of Cx43 hemichannels, release of ATP, activation of P2X7 receptor, and Ca2+ influx. However, because these Thy-1 effects occur exclusively in reactive astrocytes, we wondered whether by elevating calcium levels and promoting hemichannel opening we could prompt non-reactive astrocytes to respond to Thy-1. Cx43 immunoreactivity increased at juxta-membrane sites, where hemichannels (not gap junctions) participate in astrocyte polarization and migration stimulated by Thy-1. Also, intracellular Ca2+ increase, due to ionomycin treatment, induced hemichannel opening, but activated astrocyte migration only partially, and this limitation was overcome by pre-treatment with tumor necrosis factor (TNF) and Thy-1. Finally, αvß3 integrin formed membrane clusters after TNF stimulation or overexpression of ß3 integrin. We suggest that these microclusters are required for cells to respond to Thy-1 stimulation. Therefore, the large increase in intracellular Ca2+ and hemichannel opening induced by ionomycin are required, but not sufficient, to permit Thy-1-induced astrocyte migration. Thus, we suggest that proinflammatory stimuli prompt astrocytes to respond to migratory signals of neuronal cells.


Asunto(s)
Astrocitos/citología , Calcio/metabolismo , Movimiento Celular , Conexina 43/metabolismo , Antígenos Thy-1/metabolismo , Animales , Astrocitos/metabolismo , Señalización del Calcio , Línea Celular , Polaridad Celular , Células Cultivadas , Ratas , Ratas Wistar
4.
Virus Res ; 306: 198584, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34624404

RESUMEN

Andes Virus (ANDV) non-lytically infects pulmonary microvascular endothelial cells (PMECs) causing a severe capillary leak syndrome termed Hantavirus Pulmonary Syndrome (HPS). Basolaterally, PMECs are in contact with pericytes which play critical roles in regulating PMEC permeability and immune cell recruitment. We discovered that ANDV persistently infects primary human vascular pericytes for up to 9 days, and that PMEC monolayer permeability was increased by supernatants from ANDV-infected pericytes. Pericyte-directed PMEC permeability was consistent with the high-level secretion of the permeability factor VEGF (vascular endothelial growth factor) elicited by ANDV-infected pericytes. These findings suggest that ANDV infection of pericytes augments PMEC permeability and reveal a novel mechanism of pericyte-directed vascular barrier dysfunction that contributes to HPS and provides new therapeutic targets.


Asunto(s)
Orthohantavirus , Células Endoteliales/metabolismo , Humanos , Pericitos/metabolismo , Permeabilidad , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismo
5.
Front Cell Dev Biol ; 7: 132, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31428610

RESUMEN

Thy-1/CD90 is a glycoprotein attached to the outer face of the plasma membrane with various functions, which depend on the context of specific physiological or pathological conditions. Many of these reported functions for Thy-1/CD90 arose from studies by our group, which identified the first ligand/receptor for Thy-1/CD90 as an integrin. This finding initiated studies directed toward unveiling the molecular mechanisms that operate downstream of Thy-1/CD90 activation, and its possible interaction with proteins in the membrane plane to regulate their function. The association of Thy-1/CD90 with a number of cell surface molecules allows the formation of extra/intracellular multiprotein complexes composed of various ligands and receptors, extracellular matrix proteins, intracellular signaling proteins, and the cytoskeleton. The complexes sense changes that occur inside and outside the cells, with Thy-1/CD90 at the core of this extracellular molecular platform. Molecular platforms are scaffold-containing microdomains where key proteins associate to prominently influence cellular processes and behavior. Each component, by itself, is less effective, but when together with various scaffold proteins to form a platform, the components become more specific and efficient to convey the messages. This review article discusses the experimental evidence that supports the role of Thy-1/CD90 as a membrane-associated platform (ThyMAP).

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