Trichodysplasia spinulosa polyomavirus small T antigen synergistically modulates S6 protein translation and DNA damage response pathways to shape host cell environment

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.

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

Nature Communications ◽

10.1038/s41467-018-05354-7 ◽

2018 ◽

Vol 9 (1) ◽

Cited By ~ 10

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

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Guanine Quadruplex DNA Regulates Gamma Radiation Response of Genome Functions in the Radioresistant Bacterium Deinococcus radiodurans

Journal of Bacteriology ◽

10.1128/jb.00154-19 ◽

2019 ◽

Vol 201 (17) ◽

Cited By ~ 2

Author(s):

Shruti Mishra ◽

Reema Chaudhary ◽

Sudhir Singh ◽

Swathi Kota ◽

Hari S. Misra

Keyword(s):

Dna Damage ◽

Dna Damage Response ◽

Deinococcus Radiodurans ◽

Dna Structure ◽

Protein Translation ◽

Content Type ◽

Cellular Processes ◽

G4 Dna ◽

Guanine Quadruplex ◽

Damage Response

ABSTRACT Guanine quadruplex (G4) DNA/RNA are secondary structures that regulate the various cellular processes in both eukaryotes and bacteria. Deinococcus radiodurans, a Gram-positive bacterium known for its extraordinary radioresistance, shows a genomewide occurrence of putative G4 DNA-forming motifs in its GC-rich genome. N-Methyl mesoporphyrin (NMM), a G4 DNA structure-stabilizing drug, did not affect bacterial growth under normal conditions but inhibited the postirradiation recovery of gamma-irradiated cells. Transcriptome sequencing analysis of cells treated with both radiation and NMM showed repression of gamma radiation-responsive gene expression, which was observed in the absence of NMM. Notably, this effect of NMM on the expression of housekeeping genes involved in other cellular processes was not observed. Stabilization of G4 DNA structures mapped at the upstream of recA and in the encoding region of DR_2199 had negatively affected promoter activity in vivo, DNA synthesis in vitro and protein translation in Escherichia coli host. These results suggested that G4 DNA plays an important role in DNA damage response and in the regulation of expression of the DNA repair proteins required for radioresistance in D. radiodurans. IMPORTANCE Deinococcus radiodurans can recover from extensive DNA damage caused by many genotoxic agents. It lacks LexA/RecA-mediated canonical SOS response. Therefore, the molecular mechanisms underlying the regulation of DNA damage response would be worth investigating in this bacterium. D. radiodurans genome is GC-rich and contains numerous islands of putative guanine quadruplex (G4) DNA structure-forming motifs. Here, we showed that in vivo stabilization of G4 DNA structures can impair DNA damage response processes in D. radiodurans. Essential cellular processes such as transcription, DNA synthesis, and protein translation, which are also an integral part of the double-strand DNA break repair pathway, are affected by the arrest of G4 DNA structure dynamics. Thus, the role of DNA secondary structures in DNA damage response and radioresistance is demonstrated.

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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 ◽

10.1371/journal.pone.0116093 ◽

2015 ◽

Vol 10 (2) ◽

pp. e0116093 ◽

Cited By ~ 4

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

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Simian Virus 40 Large T Antigen Disrupts Genome Integrity and Activates a DNA Damage Response via Bub1 Binding

Journal of Virology ◽

10.1128/jvi.01515-08 ◽

2008 ◽

Vol 83 (1) ◽

pp. 117-127 ◽

Cited By ~ 91

Author(s):

Jennifer Hein ◽

Sergei Boichuk ◽

Jiaping Wu ◽

Yuan Cheng ◽

Raimundo Freire ◽

...

Keyword(s):

Dna Damage ◽

Viral Replication ◽

Dna Damage Response ◽

Simian Virus 40 ◽

Simian Virus ◽

T Antigen ◽

Genome Integrity ◽

Large T Antigen ◽

Sv40 Large T Antigen ◽

Damage Response

ABSTRACT Simian virus 40 (SV40) large T antigen (LT) is a multifunctional protein that is important for viral replication and oncogenic transformation. Previously, infection of monkey or human cells with SV40 was shown to lead to the induction of DNA damage response signaling, which is required for efficient viral replication. However, it was not clear if LT is sufficient to induce the damage response and, if so, what the genetic requirements and functional consequences might be. Here, we show that the expression of LT alone, without a replication origin, can induce key DNA damage response markers including the accumulation of γ-H2AX and 53BP1 in nuclear foci. Other DNA damage-signaling components downstream of ATM/ATR kinases were induced, including chk1 and chk2. LT also bound the Claspin mediator protein, which normally facilitates the ATR activation of chk1 and monitors cellular replication origins. Stimulation of the damage response by LT depends mainly on binding to Bub1 rather than to the retinoblastoma protein. LT has long been known to stabilize p53 despite functionally inactivating it. We show that the activation of a DNA damage response by LT via Bub1 appears to play a major role in p53 stabilization by promoting the phosphorylation of p53 at Ser15. Accompanying the DNA damage response, LT induces tetraploidy, which is also dependent on Bub1 binding. Taken together, our data suggest that LT, via Bub1 binding, breaches genome integrity mechanisms, leading to DNA damage responses, p53 stabilization, and tetraploidy.

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DNA viruses and the cellular DNA-damage response

Journal of General Virology ◽

10.1099/vir.0.044412-0 ◽

2012 ◽

Vol 93 (10) ◽

pp. 2076-2097 ◽

Cited By ~ 99

Author(s):

Andrew S. Turnell ◽

Roger J. Grand

Keyword(s):

Dna Damage ◽

Host Cell ◽

Virus Replication ◽

Dna Damage Response ◽

Cell Damage ◽

Simian Virus 40 ◽

Life Cycles ◽

Dna Viruses ◽

Damage Response ◽

Repair Pathways

It is clear that a number of host-cell factors facilitate virus replication and, conversely, a number of other factors possess inherent antiviral activity. Research, particularly over the last decade or so, has revealed that there is a complex inter-relationship between viral infection and the host-cell DNA-damage response and repair pathways. There is now a realization that viruses can selectively activate and/or repress specific components of these host-cell pathways in a temporally coordinated manner, in order to promote virus replication. Thus, some viruses, such as simian virus 40, require active DNA-repair pathways for optimal virus replication, whereas others, such as adenovirus, go to considerable lengths to inactivate some pathways. Although there is ever-increasing molecular insight into how viruses interact with host-cell damage pathways, the precise molecular roles of these pathways in virus life cycles is not well understood. The object of this review is to consider how DNA viruses have evolved to manage the function of three principal DNA damage-response pathways controlled by the three phosphoinositide 3-kinase (PI3K)-related protein kinases ATM, ATR and DNA-PK and to explore further how virus interactions with these pathways promote virus replication.

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