scholarly journals Viral hijacking of the nucleolar DNA-damage response machinery: a novel mechanism to regulate host cell biology

2017 ◽  
Author(s):  
Stephen M. Rawlinson ◽  
Tianyue Zhao ◽  
Ashley M. Rozario ◽  
Christina L. Rootes ◽  
Paul J. McMillan ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Cell Biology ◽  
Matrix Protein ◽  
Protein A ◽  
Super Resolution ◽  
Host Cells ◽  
Treacher Collins Syndrome ◽  
Damage Response ◽  
Pathogenic Viruses

ABSTRACTRecent landmark studies indicate that nucleoli play critical roles in the DNA-damage response (DDR) via interaction of DDR machinery including NBS1 with nucleolar Treacle protein, a key mediator of ribosomal RNA (rRNA) transcription and processing, implicated in Treacher-Collins syndrome. Here, using proteomics, confocal/super-resolution imaging, and infection under BSL-4 containment, we present the first report that this nucleolar DDR pathway is targeted by infectious pathogens. We find that Treacle has antiviral activity, but that matrix protein of Henipaviruses and P3 protein of rabies virus, highly pathogenic viruses of the order Mononegavirales, interact with Treacle and inhibit its function, thereby silencing rRNA biogenesis, consistent with mimicking NBS1-Treacle interaction during a DDR. These data identify a novel mechanism for viral modulation of host cells by appropriating the nucleolar DDR; this appears to have developed independently in different viruses, and represents, to our knowledge, the first direct intra-nucleolar function for proteins of any mononegavirus.

scholarly journals Crosstalk between the mTOR and DNA Damage Response Pathways in Fission Yeast

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 305
Author(s):  
John-Patrick Alao ◽  
Luc Legon ◽  
Charalampos Rallis
Keyword(s):  
Dna Damage ◽  
Fission Yeast ◽  
Dna Damage Response ◽  
Cell Biology ◽  
Environmental Changes ◽  
Energy Levels ◽  
Protein Translation ◽  
Mtor Pathway ◽  
Age Related ◽  
Damage Response

Cells have developed response systems to constantly monitor environmental changes and accordingly adjust growth, differentiation, and cellular stress programs. The evolutionarily conserved, nutrient-responsive, mechanistic target of rapamycin signaling (mTOR) pathway coordinates basic anabolic and catabolic cellular processes such as gene transcription, protein translation, autophagy, and metabolism, and is directly implicated in cellular and organismal aging as well as age-related diseases. mTOR mediates these processes in response to a broad range of inputs such as oxygen, amino acids, hormones, and energy levels, as well as stresses, including DNA damage. Here, we briefly summarize data relating to the interplays of the mTOR pathway with DNA damage response pathways in fission yeast, a favorite model in cell biology, and how these interactions shape cell decisions, growth, and cell-cycle progression. We, especially, comment on the roles of caffeine-mediated DNA-damage override. Understanding the biology of nutrient response, DNA damage and related pharmacological treatments can lead to the design of interventions towards improved cellular and organismal fitness, health, and survival.

scholarly journals Viral regulation of host cell biology by hijacking of the nucleolar DNA-damage response

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Stephen M. Rawlinson ◽  
Tianyue Zhao ◽  
Ashley M. Rozario ◽  
Christina L. Rootes ◽  
Paul J. McMillan ◽  
...  
Keyword(s):  
Dna Damage ◽  
Host Cell ◽  
Dna Damage Response ◽  
Cell Biology ◽  
Damage Response

scholarly journals Treacher Collins syndrome TCOF1 protein cooperates with NBS1 in the DNA damage response

2014 ◽  
Vol 111 (52) ◽  
pp. 18631-18636 ◽  
Author(s):  
Alberto Ciccia ◽  
Jen-Wei Huang ◽  
Lior Izhar ◽  
Mathew E. Sowa ◽  
J. Wade Harper ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Treacher Collins Syndrome ◽  
Damage Response

scholarly journals SARS-CoV-2 triggers DNA damage response in Vero E6 cells

2021 ◽  
Author(s):  
Joshua Victor ◽  
Jamie Deutsch ◽  
Annalis Whitaker ◽  
Erica N. Lamkin ◽  
Anthony March ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Host Cells ◽  
Kidney Cells ◽  
The Novel ◽  
African Green Monkey Kidney ◽  
Downstream Effector ◽  
Damage Response ◽  
Green Monkey ◽  
Infected Cells

AbstractThe novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus responsible for the current COVID-19 pandemic and has now infected more than 200 million people with more than 4 million deaths globally. Recent data suggest that symptoms and general malaise may continue long after the infection has ended in recovered patients, suggesting that SARS-CoV-2 infection has profound consequences in the host cells. Here we report that SARS-CoV-2 infection can trigger a DNA damage response (DDR) in African green monkey kidney cells (Vero E6). We observed a transcriptional upregulation of the Ataxia telangiectasia and Rad3 related protein (ATR) in infected cells. In addition, we observed enhanced phosphorylation of CHK1, a downstream effector of the ATR DNA damage response, as well as H2AX. Strikingly, SARS-CoV-2 infection lowered the expression of TRF2 shelterin-protein complex, and reduced telomere lengths in infected Vero E6 cells. Thus, our observations suggest SARS-CoV-2 may have pathological consequences to host cells beyond evoking an immunopathogenic immune response.

scholarly journals Simian Virus Large T Antigen Interacts with the N-Terminal Domain of the 70 kD Subunit of Replication Protein A in the Same Mode as Multiple DNA Damage Response Factors

PLoS ONE ◽  
2015 ◽  
Vol 10 (2) ◽  
pp. e0116093 ◽  
Author(s):  
Boting Ning ◽  
Michael D. Feldkamp ◽  
David Cortez ◽  
Walter J. Chazin ◽  
Katherine L. Friedman ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Protein A ◽  
Replication Protein A ◽  
Simian Virus ◽  
T Antigen ◽  
Replication Protein ◽  
Large T Antigen ◽  
Response Factors ◽  
Damage Response

scholarly journals Ataxia telangiectasia mutated- and Rad3-related kinase drives both the early and the late DNA-damage response to the monofunctional antitumour alkylator S23906

2011 ◽  
Vol 437 (1) ◽  
pp. 63-73 ◽  
Author(s):  
Daniele G. Soares ◽  
Aude Battistella ◽  
Céline J. Rocca ◽  
Renata Matuo ◽  
João A. P. Henriques ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Anticancer Agents ◽  
Ataxia Telangiectasia ◽  
Kinase Inhibitors ◽  
Protein A ◽  
Initial Response ◽  
Synergistic Activity ◽  
Ataxia Telangiectasia Mutated ◽  
Damage Response

Numerous anticancer agents and environmental mutagens target DNA. Although all such compounds interfere with the progression of the replication fork and inhibit DNA synthesis, there are marked differences in the DNA-damage response pathways they trigger, and the relative impact of the proximal or the distal signal transducers on cell survival is mainly lesion-specific. Accordingly, checkpoint kinase inhibitors in current clinical development show synergistic activity with some DNA-targeting agents, but not with others. In the present study, we characterize the DNA-damage response to the antitumour acronycine derivative S23906, which forms monofunctional adducts with guanine residues in the minor groove of DNA. S23906 exposure is accompanied by specific recruitment of RPA (replication protein A) at replication sites and rapid Chk1 activation. In contrast, neither MRN (Mre11-Rad50-Nbs1) nor ATM (ataxia-telangiectasia mutated), contributes to the initial response to S23906. Interestingly, genetic attenuation of ATR (ATM- and Ras3-related) activity inhibits not only the early phosphorylation of histone H2AX and Chk1, but also interferes with the late phosphorylation of Chk2. Moreover, loss of ATR function or pharmacological inhibition of the checkpoint kinases by AZD7762 is accompanied by abrogation of the S-phase arrest and increased sensitivity towards S23906. These findings identify ATR as a central co-ordinator of the DNA-damage response to S23906, and provide a mechanistic rationale for combinations of S23906 and similar agents with checkpoint abrogators.

scholarly journals Structural Analysis of Replication Protein A Recruitment of the DNA Damage Response Protein SMARCAL1

Biochemistry ◽  
2014 ◽  
Vol 53 (18) ◽  
pp. 3052-3061 ◽  
Author(s):  
Michael D. Feldkamp ◽  
Aaron C. Mason ◽  
Brandt F. Eichman ◽  
Walter J. Chazin
Keyword(s):  
Dna Damage ◽  
Structural Analysis ◽  
Dna Damage Response ◽  
Protein A ◽  
Replication Protein A ◽  
Replication Protein ◽  
Damage Response

scholarly journals A short HBV RNA region induces RNR-R2 expression in non-cycling cells and in primary human hepatocytes

2018 ◽  
Author(s):  
Inna Ricardo-Lax ◽  
Karin Broennimann ◽  
Julia Adler ◽  
Eleftherios Michailidis ◽  
Ype P de Jong ◽  
...  
Keyword(s):  
Dna Damage ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Dna Damage Response ◽  
Human Hepatocytes ◽  
Host Cells ◽  
Primary Human Hepatocytes ◽  
B Virus ◽  
Damage Response ◽  
Cellular Dna

AbstractHepatitis B virus infects non-dividing cells in which dNTPs are scarce. HBV replication requires dNTPs. To cope with this constraint the virus induces the DNA damage response (DDR) pathway culminating in RNR-R2 expression and the generation of an active RNR holoenzyme, the key regulator of dNTP levels. Previously we reported that the HBx open reading frame (ORF) triggers this pathway. Unexpectedly however, we report here that the production of HBx protein is not essential. We found that a small region of 125 bases within the HBx transcript is sufficient to induce RNR-R2 expression in growth arrested HepG2 cells and in primary human hepatocytes (PHH). The observed HBx embedded regulatory element is named ERE. We demonstrate that ERE is functional as a positive strand RNA polymerase-II transcript. Remarkably, ERE is sufficient to induce the Chk1-E2F1-RNR-R2 DDR pathway, previously reported to be activated by HBV. Furthermore, we found that ERE activates ATR but not ATM in eliciting this DDR pathway in upregulating RNR-R2. These findings demonstrate the multitasking role of HBV transcripts in mediating virus-host cell interaction, a mechanism that explains how such a small genome effectively serves such a pervasive virus.Author summaryThe hepatitis B virus (HBV) infects the human liver and over 250 million people worldwide are chronically infected with HBV and at risk for cirrhosis and liver cancer. HBV has a very small DNA genome with only four genes, much fewer than other viruses. For propagation the virus consumes dNTPs, the building blocks of DNA, in much higher amounts than the infected cells provide. To cope with this constraint, the virus manipulates the cells to increase the production of dNTPs. We found that the virus activates the cellular response to DNA damage upon which the cells increase the production of dNTPs, but instead of repairing cellular DNA, the virus uses them for production of its own DNA. Usually viruses manipulate host cells with one or more of their unique proteins, however the small HBV genome cannot afford having such a unique gene and protein. Instead, we found that here the virus relies on RNA to manipulate the host cells. Our findings highlight the unprecedented principle of a multitasking viral RNA that is not only designed to be translated into proteins but also harbors an independent role in activating the cellular DNA damage response.

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