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dna damage and virus

Catharina Majer, Jan Moritz Schüssler, Renate König
SAMHD1 was initially described for its ability to efficiently restrict HIV-1 replication in myeloid cells and resting CD4+ T cells. However, a growing body of evidence suggests that SAMHD1-mediated restriction is by far not limited to lentiviruses, but seems to be a general concept that applies to most retroviruses and at least a number of DNA viruses. SAMHD1 anti-viral activity was long believed to be solely due to its ability to deplete cellular dNTPs by enzymatic degradation. However, since its discovery, several new functions have been attributed to SAMHD1...
March 16, 2019: Medical Microbiology and Immunology
Khaled Aziz, Jazeel F Limzerwala, Ines Sturmlechner, Erin Hurley, Cheng Zhang, Karthik B Jeganathan, Grace Nelson, Steve Bronk, Raul Fierro Velasco, Erik-Jan van Deursen, Daniel R O'Brien, Jean-Pierre A Kocher, Sameh A Youssef, Janine H van Ree, Alain de Bruin, Hilda van den Bos, Diana C J Spierings, Floris Foijer, Bart van de Sluis, Lewis R Roberts, Gregory Gores, Hu Li, Jan M van Deursen
BACKGROUND & AIMS: The CCNE1 locus, which encodes cyclin E1, is amplified in many types of cancer cells and is activated in hepatocellular carcinomas (HCCs) from patients infected with hepatitis B virus or adeno-associated virus type 2, due to integration of the virus nearby. We investigated cell cycle and oncogenic effects of cyclin E1 overexpression in tissues of mice. METHODS: We generated mice with doxycycline-inducible expression of Ccne1 (Ccne1T mice) and activated overexpression of cyclin E1 from age 3 weeks onwards...
March 13, 2019: Gastroenterology
B Nandi, S Talluri, S Kumar, C Yenumula, J S Gold, R Prabhala, N C Munshi, M A Shammas
A variety of factors, whether extracellular (mutagens/carcinogens and viruses in the environment, chronic inflammation and radiation associated with the environment and/or electronic devices/machines) and/or intracellular (oxidative metabolites of food, oxidative stress due to inflammation, acid production, replication stress, DNA replication/repair errors, and certain hormones, cytokines, growth factors), pose a constant threat to the genomic integrity of a living cell. However, in the normal cellular environment multiple biological pathways including DNA repair, cell cycle, apoptosis and the immune system work in a precise, regulated (tightly controlled), timely and concerted manner to ensure genomic integrity, stability and proper functioning of a cell...
April 2019: Journal of Translational Science
Guozhi Bian, Haibin Ma, Mengping Luo, Fengping Gong, Bo Li, Guiping Wang, Mudassar Mohiuddin, Ming Liao, Jianfeng Yuan
BACKGROUND: Since early 2015, mule duck and Cherry Valley duck flocks have been suffering from short beak and dwarfism syndrome. This widely spreading infectious disease is characterized by growth retardation, smaller beak and tarsus with high morbidity and low mortality rate. For better understanding, we identified and characterized virus isolates named AH and GD from diseased Cherry Valley duck and mule duck flocks and investigated the damage caused by novel parvovirus-related virus (NGPV) to tissues and organs, including kidney, brain, pancreas, liver, spleen, bursa of fabricius and myocardial tissues...
March 12, 2019: BMC Veterinary Research
Randi M Mackler, Nathan D Jones, Anne M Gardner, Miguel A Lopez, Cecil J Howard, Richard Fishel, Kristine E Yoder
Eukaryotic DNA binding proteins must access genomic DNA that is packaged into chromatin in vivo. During a productive infection, retroviral integrases (IN) must similarly interact with chromatin to integrate the viral cDNA genome. Here we examine the role of nucleosome DNA unwrapping in the retroviral integrase search for a target site. These studies utilized PFV intasomes that are comprised of a tetramer of PFV IN with two oligomers mimicking the viral cDNA ends. Modified recombinant human histones were used to generate nucleosomes with increased unwrapping rates at different DNA regions...
2019: PloS One
Takayuki Fujii, Kei-Ichiro Takase, Hiroyuki Honda, Nobutoshi Kawamura, Ryo Yamasaki, Michiyo Urata, Takeshi Uchiumi, Toru Iwaki, Jun-Ichi Kira
Oral nucleoside analogs (NAs) reduce hepatitis B virus (HBV) replication by inhibiting HBV DNA polymerase. However, NAs can also affect human mitochondrial DNA (mtDNA) polymerase, which can lead to mtDNA depletion (quantitative abnormality). Indeed, several mitochondrial myopathy cases have been reported in which a reduced mtDNA copy number was induced by oral NAs for hepatitis B. Herein, we report a case of toxic myopathy with multiple mtDNA deletions (qualitative abnormality) associated with long-term use of NAs for hepatitis B...
March 7, 2019: Neuropathology: Official Journal of the Japanese Society of Neuropathology
Wei-Chen Huang, Hui-Shang Chi, Yi-Chao Lee, Yu-Chun Lo, Ta-Chung Liu, Min-Yu Chiang, Hsu-Yan Chen, Ssu-Ju Li, You-Yin Chen, San-Yuan Chen
Optogenetics is a recently established neuromodulation technique that can apply photostimulation to manipulate neurons with high temporal and spatial precision. However, sequent genetic and optic insertion with double brain implantation tends to cause the excessive tissue damages. In addition, incorporating light-sensitive genes requires the utilization of viral vectors, which remains one of the safety concerns. Here, combined with device fabrication design, nanotechnology, and cell targeting technology, a new gene-embedded optoelectrode arrays for neural implantation was developed to enable spatiotemporal electroporation (EP) for gene delivery/transfection, photomodulation, and synchronous electrical monitoring of neural signals in the brain via one-time implantation...
March 7, 2019: ACS Applied Materials & Interfaces
Xiang Gui, Hui Yang, Tuo Li, Xiaojun Tan, Peiqing Shi, Minghao Li, Fenghe Du, Zhijian J Chen
Cyclic GMP-AMP (cGAMP) synthase (cGAS) detects infections or tissue damage by binding to microbial or self DNA in the cytoplasm1 . Upon binding DNA, cGAS produces cGAMP that binds to and activates the adaptor protein STING, which then activates the kinases IKK and TBK1 to induce interferons and other cytokines2-6 . Here we report that STING also activates autophagy through a mechanism that is independent of TBK1 activation and interferon induction. Upon binding cGAMP, STING translocates to the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) and the Golgi in a process that is dependent on the COP-II complex and ARF GTPases...
March 6, 2019: Nature
Andrea Michelle Soriano, Leandro Crisostomo, Megan Mendez, Drayson Graves, Jasmine Rae Frost, Oladunni Olanubi, Peter F Whyte, Patrick Hearing, Peter Pelka
Human adenovirus expresses several early proteins that control various aspects of the viral replication program, including an orchestrated expression of viral genes. Two of the earliest viral transcriptional units activated after viral genome entry into the host cell nucleus are the E1 and E4 units that each express a variety of proteins. Chief amongst these are the E1A proteins that function to reprogram the host cell and activate transcription of all other viral genes. The E4 gene encodes multiple proteins including E4orf3, which functions to disrupt cellular antiviral defenses, including the DNA damage response pathway and activation of antiviral genes...
March 6, 2019: Journal of Virology
Keren Nebenzahl-Sharon, Hassan Shalata, Rakefet Sharf, Jana Amer, Hanan Khoury-Haddad, Sook-Young Sohn, Nabieh Ayoub, Patrick Hearing, Tamar Kleinberger
The adenovirus (Ad) E4orf4 protein contributes to viral-induced inhibition of the DNA damage response (DDR) by reducing ATM and ATR signaling. Consequently E4orf4 inhibits DNA repair and sensitizes transformed cells to killing by DNA damaging drugs. Inhibition of ATM and ATR signaling contributes to the efficiency of virus replication and may provide one explanation for the cancer selectivity of cell death induced by expression of E4orf4 alone. In this report we investigate a direct interaction of E4orf4 with the DDR...
March 6, 2019: Journal of Virology
Pengfei Cao, Meili Zhang, Lujuan Wang, Buqing Sai, Jiuqi Tang, Zhaohui Luo, Cijun Shuai, Liyang Zhang, Zheng Li, Yanjin Wang, Guiyuan Li, Juanjuan Xiang
March 1, 2019: BMC Cancer
M M Brosnahan, M A Al Abri, S A Brooks, D F Antczak, N Osterrieder
Equine herpesvirus type 1 (EHV-1)-induced myeloencephalopathy (EHM) is a neurologic disease of horses that represents one outcome of infection. The neurologic form of disease occurs in a subset of infected horses when virus-induced endothelial cell damage triggers vasculitis and subsequent ischemic insult to the central nervous system. EHM causes considerable animal suffering and economic loss for the horse industry. Virus polymorphisms have been previously associated with disease outcome but cannot fully explain why only some horses develop EHM...
March 2019: Veterinary Journal
Diana Raquel Rodríguez-Rodríguez, Ramiro Ramírez-Solís, Mario Alberto Garza-Elizondo, María De Lourdes Garza-Rodríguez, Hugo Alberto Barrera-Saldaña
Genome editing reemerged in 2012 with the development of CRISPR/Cas9 technology, which is a genetic manipulation tool derived from the defense system of certain bacteria against viruses and plasmids. This method is easy to apply and has been used in a wide variety of experimental models, including cell lines, laboratory animals, plants, and even in human clinical trials. The CRISPR/Cas9 system consists of directing the Cas9 nuclease to create a site‑directed double‑strand DNA break using a small RNA molecule as a guide...
February 26, 2019: International Journal of Molecular Medicine
Kimberly D Erickson, Robert L Garcea
JCV is a human polyomavirus (PyV) that establishes a persistent infection in its host. Current immunomodulatory therapies, such as Natalizumab for multiple sclerosis, can result in JCV reactivation, leading to the debilitating brain disease progressive multifocal leukoencephalopathy (PML). JCV is among the viruses that recruit and modulate the host DNA damage response (DDR) to replicate its genome. We have identified host proteins recruited to the nuclear sites of JC viral DNA (vDNA) replication using three cell types susceptible to infection in vitro...
February 2019: Virology
Sook-Young Sohn, Patrick Hearing
Regulation of a variety of different cellular processes, including posttranslational modifications, is critical for the ability of many viruses to replicate efficiently within host cells. The adenovirus (Ad) E4-ORF3 protein assembles into polymers and forms a unique nuclear scaffold that leads to the relocalization and sequestration of cellular proteins, including small ubiquitin-like modifiers (SUMOs). Previously, we showed that E4-ORF3 functions as a SUMO E3 ligase of transcriptional intermediary factor-1 gamma (TIF-1γ) and promotes poly-SUMO chain formation...
February 26, 2019: MBio
Susanne Kimeswenger, Ulrike Mann, Christoph Hoeller, Dagmar Foedinger, Christian Jantschitsch
Targeted therapy with the BRAF inhibitors vemurafenib and dabrafenib is an effective treatment regimen in patients with advanced melanoma carrying the BRAF V600E mutation. A common side effect is an enhanced rate of nonmelanoma skin cancer (NMSC). BRAF inhibition leads to a paradoxical enhanced MAPK signalling in BRAF wild-type cells, which might in part be responsible for the enhanced NMSC burden. It is known that disturbances of DNA repair result in an increased rate of NMSC. In the present study, it was investigated whether BRAF inhibitors might interfere with the repair of ultraviolet radiation-induced DNA damage in vitro...
April 2019: Melanoma Research
Takayuki Abe, Sagi D Shapira
In mammals, cytosolic detection of nucleic acids is critical in initiating innate antiviral responses against invading pathogens (like bacteria, viruses, fungi and parasites). These programs are mediated by multiple cytosolic and endosomal sensors and adaptor molecules (c-GAS/STING axis and TLR9/MyD88 axis, respectively) and lead to the production of type I interferons (IFNs), pro-inflammatory cytokines, and chemokines. While the identity and role of multiple pattern recognition receptors (PRRs) have been elucidated, such immune surveillance systems must be tightly regulated to limit collateral damage and prevent aberrant responses to self- and non-self-nucleic acids...
2019: International Review of Cell and Molecular Biology
Miroslaw Mack Mackiewicz, Cassia Overk, Cristian L Achim, Eliezer Masliah
People over the age of 50 are the fastest growing segment of the HIV-infected population in the USA. Although antiretroviral therapy has remarkable success controlling the systemic HIV infection, HIV-associated neurocognitive disorder (HAND) prevalence has increased or remained the same among this group, and cognitive deficits appear more severe in aged patients with HIV. The mechanisms of HAND in the aged population are not completely understood; a leading hypothesis is that aged individuals with HIV might be at higher risk of developing Alzheimer's disease (AD) or one of the AD-related dementias (ADRD)...
February 21, 2019: Journal of Neurovirology
Xue Lian, Chenyi Bao, Xueqi Li, Xunhai Zhang, Hongjun Chen, Yong-Sam Jung, Yingjuan Qian
Oncogenic virus replication often leads to genomic instability, causing DNA damage and inducing the DNA damage response (DDR) pathway. The DDR is a cellular pathway that senses DNA damage and regulates the cell cycle to maintain genomic stability. Therefore, the DDR pathway is critical for the viral lifecycle and tumorigenesis. Marek's disease virus (MDV), an α-herpesvirus that causes lymphoma in chickens, has been shown to induce DNA damage in infected cells. However, the interaction between MDV and host DDR is unclear...
February 20, 2019: Journal of Virology
Baki Akgül, Matthias Kirschberg, Alan Storey, Martin Hufbauer
Human papillomavirus 8 (HPV8) is associated with the development of squamous cell carcinomas (SCC) of the skin. HPV-infected keratinocytes are able to over-ride normal checkpoint control mechanisms and sustain cell cycle activity, allowing for synthesis of cellular proteins necessary for viral genome amplification. To study how HPV8 may disrupt cell-cycle control, we analysed the impact of HPV8 early gene expression on one of the key regulators of cell cycle and DNA damage response, checkpoint kinase-1 (CHK1)...
February 20, 2019: International Journal of Cancer. Journal International du Cancer
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