scholarly journals Avian Sarcoma and Leukosis Virus Cytopathic Effect in the Absence of TVB Death Domain Signaling

2005 ◽  
Vol 79 (13) ◽  
pp. 8243-8248 ◽  
Author(s):  
Sara Klucking ◽  
Asha S. Collins ◽  
John A. T. Young
Keyword(s):  
Dna Damage ◽  
Signaling Pathways ◽  
Dna Damage Response ◽  
Cytopathic Effect ◽  
Tumor Necrosis Factor Receptor ◽  
Death Domain ◽  
Trail Receptors ◽  
Damage Response ◽  
Cellular Dna ◽  
Avian Sarcoma

ABSTRACT The cytopathic effect (CPE) seen with some subgroups of avian sarcoma and leukosis virus (ASLV) is associated with viral Env activation of the death-promoting activity of TVB (a tumor necrosis factor receptor-related receptor that is most closely related to mammalian TNF-related apoptosis-inducing ligand [TRAIL] receptors) and with viral superinfection leading to unintegrated viral DNA (UVD) accumulation, which is presumed to activate a cellular DNA damage response. In this study, we employed cells that express signaling-deficient ASLV receptors to demonstrate that an ASLV CPE can be uncoupled from the death-promoting functions of the TVB receptor. However, these cell-killing events were associated with much higher levels of viral superinfection and DNA accumulation than those seen when the virus used signaling-competent TVB receptors. These findings suggest that a putative cellular DNA damage response that is activated by UVD accumulation might act in concert with the death-signaling pathways activated by Env-TVB interactions to trigger cell death. Such a model is consistent with the well-established synergy that exists between TRAIL-signaling pathways and DNA damage responses which is currently being exploited in cancer therapy regimens.

scholarly journals Adenovirus E1B 55-Kilodalton Protein Targets SMARCAL1 for Degradation during Infection and Modulates Cellular DNA Replication

2019 ◽  
Vol 93 (13) ◽  
Author(s):  
Reshma Nazeer ◽  
Fadi S. I. Qashqari ◽  
Abeer S. Albalawi ◽  
Ann Liza Piberger ◽  
Maria Teresa Tilotta ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Replication ◽  
Viral Replication ◽  
Signaling Pathways ◽  
Dna Damage Response ◽  
Replication Fork ◽  
Dependent Manner ◽  
Damage Response ◽  
Adenovirus E1b ◽  
Cellular Dna

ABSTRACT Here, we show that the cellular DNA replication protein and ATR substrate SMARCAL1 is recruited to viral replication centers early during adenovirus infection and is then targeted in an E1B-55K/E4orf6- and cullin RING ligase-dependent manner for proteasomal degradation. In this regard, we have determined that SMARCAL1 is phosphorylated at S123, S129, and S173 early during infection in an ATR- and CDK-dependent manner, and that pharmacological inhibition of ATR and CDK activities attenuates SMARCAL1 degradation. SMARCAL1 recruitment to viral replication centers was shown to be largely dependent upon SMARCAL1 association with the RPA complex, while Ad-induced SMARCAL1 phosphorylation also contributed to SMARCAL1 recruitment to viral replication centers, albeit to a limited extent. SMARCAL1 was found associated with E1B-55K in adenovirus E1-transformed cells. Consistent with its ability to target SMARCAL1, we determined that E1B-55K modulates cellular DNA replication. As such, E1B-55K expression initially enhances cellular DNA replication fork speed but ultimately leads to increased replication fork stalling and the attenuation of cellular DNA replication. Therefore, we propose that adenovirus targets SMARCAL1 for degradation during infection to inhibit cellular DNA replication and promote viral replication. IMPORTANCE Viruses have evolved to inhibit cellular DNA damage response pathways that possess antiviral activities and utilize DNA damage response pathways that possess proviral activities. Adenovirus has evolved, primarily, to inhibit DNA damage response pathways by engaging with the ubiquitin-proteasome system and promoting the degradation of key cellular proteins. Adenovirus differentially regulates ATR DNA damage response signaling pathways during infection. The cellular adenovirus E1B-55K binding protein E1B-AP5 participates in ATR signaling pathways activated during infection, while adenovirus 12 E4orf6 negates Chk1 activation by promoting the proteasome-dependent degradation of the ATR activator TOPBP1. The studies detailed here indicate that adenovirus utilizes ATR kinase and CDKs during infection to promote the degradation of SMARCAL1 to attenuate normal cellular DNA replication. These studies further our understanding of the relationship between adenovirus and DNA damage and cell cycle signaling pathways during infection and establish new roles for E1B-55K in the modulation of cellular DNA replication.

scholarly journals Targeting Protein-Protein Interactions in the DNA Damage Response Pathways for Cancer Chemotherapy

2021 ◽  
Author(s):  
Kerry Silva McPherson ◽  
Dmitry Korzhnev
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Protein Interactions ◽  
Cell Cycle Progression ◽  
Protein Protein Interactions ◽  
Cycle Progression ◽  
Damage Recognition ◽  
Damage Response ◽  
Cellular Dna ◽  
Dna Damage Recognition

Cellular DNA damage response (DDR) is an extensive signaling network that orchestrates DNA damage recognition, repair and avoidance, cell cycle progression and cell death. DDR alternation is a hallmark of...

scholarly journals HPV16-E2 induces prophase arrest and activates the cellular DNA damage response in vitro and in precursor lesions of cervical carcinoma

Oncotarget ◽  
2015 ◽  
Vol 6 (33) ◽  
pp. 34979-34991 ◽  
Author(s):  
Yuezhen Xue ◽  
Shen Yon Toh ◽  
Pingping He ◽  
Thimothy Lim ◽  
Diana Lim ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Cervical Carcinoma ◽  
Precursor Lesions ◽  
Damage Response ◽  
Cellular Dna

scholarly journals High Fidelity Deep Sequencing Reveals No Effect of ATM, ATR, and DNA-PK Cellular DNA Damage Response Pathways on Adenovirus Mutation Rate

Viruses ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 938 ◽  
Author(s):  
Risso-Ballester ◽  
Sanjuán
Keyword(s):  
Dna Damage ◽  
Protein Kinase ◽  
Dna Damage Response ◽  
Deep Sequencing ◽  
Molecular Mechanisms ◽  
Spontaneous Mutation ◽  
High Fidelity ◽  
Dna Viruses ◽  
Damage Response ◽  
Cellular Dna

Most DNA viruses exhibit relatively low rates of spontaneous mutation. However, the molecular mechanisms underlying DNA virus genetic stability remain unclear. In principle, mutation rates should not depend solely on polymerase fidelity, but also on factors such as DNA damage and repair efficiency. Most eukaryotic DNA viruses interact with the cellular DNA damage response (DDR), but the role of DDR pathways in preventing mutations in the virus has not been tested empirically. To address this goal, we serially transferred human adenovirus type 5 in cells in which the telangiectasia-mutated PI3K-related protein kinase (ATM), the ATM/Rad3-related (ATR) kinase, and the DNA-dependent protein kinase (DNA-PK) were chemically inactivated, as well as in control cells displaying normal DDR pathway functioning. High-fidelity deep sequencing of these viral populations revealed mutation frequencies in the order of one-millionth, with no detectable effect of the inactivation of DDR mediators ATM, ATR, and DNA-PK on adenovirus sequence variability. This suggests that these DDR pathways do not play a major role in determining adenovirus genetic diversity.

scholarly journals DNA-PKcs: A Multi-Faceted Player in DNA Damage Response

2020 ◽  
Vol 11 ◽  
Author(s):  
Xiaoqiao Yue ◽  
Chenjun Bai ◽  
Dafei Xie ◽  
Teng Ma ◽  
Ping-Kun Zhou
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Cell Cycle Checkpoints ◽  
Dna Double Strand Breaks ◽  
Phosphatidylinositol 3 Kinase ◽  
Strand Breaks ◽  
Damage Response ◽  
Functional Complex ◽  
Dependent Protein ◽  
Cellular Dna

DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a member of the phosphatidylinositol 3-kinase related kinase family, which can phosphorylate more than 700 substrates. As the core enzyme, DNA-PKcs forms the active DNA-PK holoenzyme with the Ku80/Ku70 heterodimer to play crucial roles in cellular DNA damage response (DDR). Once DNA double strand breaks (DSBs) occur in the cells, DNA-PKcs is promptly recruited into damage sites and activated. DNA-PKcs is auto-phosphorylated and phosphorylated by Ataxia-Telangiectasia Mutated at multiple sites, and phosphorylates other targets, participating in a series of DDR and repair processes, which determine the cells’ fates: DSBs NHEJ repair and pathway choice, replication stress response, cell cycle checkpoints, telomeres length maintenance, senescence, autophagy, etc. Due to the special and multi-faceted roles of DNA-PKcs in the cellular responses to DNA damage, it is important to precisely regulate the formation and dynamic of its functional complex and activities for guarding genomic stability. On the other hand, targeting DNA-PKcs has been considered as a promising strategy of exploring novel radiosensitizers and killing agents of cancer cells. Combining DNA-PKcs inhibitors with radiotherapy can effectively enhance the efficacy of radiotherapy, offering more possibilities for cancer therapy.

scholarly journals Complex DNA Damage Induced by High Linear Energy Transfer Alpha-Particles and Protons Triggers a Specific Cellular DNA Damage Response

2018 ◽  
Vol 100 (3) ◽  
pp. 776-784 ◽  
Author(s):  
Rachel J. Carter ◽  
Catherine M. Nickson ◽  
James M. Thompson ◽  
Andrzej Kacperek ◽  
Mark A. Hill ◽  
...  
Keyword(s):  
Dna Damage ◽  
Energy Transfer ◽  
Dna Damage Response ◽  
Linear Energy Transfer ◽  
Alpha Particles ◽  
Damage Response ◽  
Cellular Dna ◽  
High Linear Energy Transfer

Abstract 497: Higher nucleolar index of nucleolin as an indicator of aberrant cellular DNA damage response (DDR)

2017 ◽  
Author(s):  
Iqra Nadeem ◽  
Amna Aslam ◽  
Jingyuan Wang ◽  
Anna Kozlova ◽  
Danielle Gordon ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Damage Response ◽  
Cellular Dna

scholarly journals Activation of the Cellular DNA Damage Response in the Absence of DNA Lesions

Science ◽  
2008 ◽  
Vol 320 (5882) ◽  
pp. 1507-1510 ◽  
Author(s):  
E. Soutoglou ◽  
T. Misteli
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Dna Lesions ◽  
Damage Response ◽  
Cellular Dna
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