scholarly journals HTLV-1 Tax Oncoprotein Subverts the Cellular DNA Damage Response via Binding to DNA-dependent Protein Kinase

2008 ◽  
Vol 283 (52) ◽  
pp. 36311-36320 ◽  
Author(s):  
Sarah S. Durkin ◽  
Xin Guo ◽  
Kimberly A. Fryrear ◽  
Valia T. Mihaylova ◽  
Saurabh K. Gupta ◽  
...  
Keyword(s):  
Dna Damage ◽  
Protein Kinase ◽  
Dna Damage Response ◽  
Dependent Protein Kinase ◽  
Damage Response ◽  
Dependent Protein ◽  
Cellular Dna

scholarly journals Nuclear localized Raf1 isoform alters DNA‐dependent protein kinase activity and the DNA damage response

2018 ◽  
Vol 33 (1) ◽  
pp. 1138-1150 ◽  
Author(s):  
Benjamin R. Nixon ◽  
Sara C. Sebag ◽  
Michael S. Glennon ◽  
Eric J. Hall ◽  
Emily S. Kounlavong ◽  
...  
Keyword(s):  
Dna Damage ◽  
Protein Kinase ◽  
Dna Damage Response ◽  
Kinase Activity ◽  
Protein Kinase Activity ◽  
Dependent Protein Kinase ◽  
Damage Response ◽  
Dependent Protein

scholarly journals Adeno-Associated Virus Replication Induces a DNA Damage Response Coordinated by DNA-Dependent Protein Kinase

2009 ◽  
Vol 83 (12) ◽  
pp. 6269-6278 ◽  
Author(s):  
Rachel A. Schwartz ◽  
Christian T. Carson ◽  
Christine Schuberth ◽  
Matthew D. Weitzman
Keyword(s):  
Dna Damage ◽  
Protein Kinase ◽  
Dna Damage Response ◽  
Dependent Protein Kinase ◽  
Adeno Associated Virus ◽  
Host Cell Response ◽  
Rep Proteins ◽  
Damage Response ◽  
Dependent Protein ◽  
Cellular Replication

ABSTRACT The parvovirus adeno-associated virus (AAV) contains a small single-stranded DNA genome with inverted terminal repeats that form hairpin structures. In order to propagate, AAV relies on the cellular replication machinery together with functions supplied by coinfecting helper viruses such as adenovirus (Ad). Here, we examined the host cell response to AAV replication in the context of Ad or Ad helper proteins. We show that AAV and Ad coinfection activates a DNA damage response (DDR) that is distinct from that seen during Ad or AAV infection alone. The DDR was also triggered when AAV replicated in the presence of minimal Ad helper proteins. We detected autophosphorylation of the kinases ataxia telangiectasia mutated (ATM) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and signaling to downstream targets SMC1, Chk1, Chk2, H2AX, and XRCC4 and multiple sites on RPA32. The Mre11 complex was not required for activation of the DDR to AAV infection. Additionally, we found that DNA-PKcs was the primary mediator of damage signaling in response to AAV replication. Immunofluorescence revealed that some activated damage proteins were found in a pan-nuclear pattern (phosphorylated ATM, SMC1, and H2AX), while others such as DNA-PK components (DNA-PKcs, Ku70, and Ku86) and RPA32 accumulated at AAV replication centers. Although expression of the large viral Rep proteins contributed to some damage signaling, we observed that the full response required replication of the AAV genome. Our results demonstrate that AAV replication in the presence of Ad helper functions elicits a unique damage response controlled by DNA-PK.

scholarly journals Steroidogenic Factor 1 (NR5A1) Maintains Centrosome Homeostasis in Steroidogenic Cells by Restricting Centrosomal DNA-Dependent Protein Kinase Activation

2012 ◽  
Vol 33 (3) ◽  
pp. 476-484 ◽  
Author(s):  
Chia-Yih Wang ◽  
Yung-Hsin Kao ◽  
Pao-Yen Lai ◽  
Wei-Yi Chen ◽  
Bon-chu Chung
Keyword(s):  
Dna Damage ◽  
Protein Kinase ◽  
Dna Damage Response ◽  
Nuclear Dna ◽  
Cyclin A ◽  
Dependent Protein Kinase ◽  
Steroidogenic Factor 1 ◽  
Damage Response ◽  
Dependent Protein ◽  
Steroidogenic Cells

ABSTRACTSteroidogenic factor 1 (SF-1 or NR5A1) is a nuclear receptor that controls adrenogenital cell growth and differentiation. Adrenogenital primordial cells fromSF-1knockout mice die of apoptosis, but the mechanism by which SF-1 regulates cell survival is not entirely clear. Besides functioning in the nucleus, SF-1 also resides in the centrosome and controls centrosome homeostasis. Here, we show that SF-1 restricts centrosome overduplication by inhibiting aberrant activation of DNA-dependent protein kinase (DNA-PK) in the centrosome. SF-1 was found to be associated with Ku70/Ku80 only in the centrosome, sequestering them from the catalytic subunit of DNA-PK (DNA-PKcs). In the absence of SF-1, DNA-PKcs was recruited to the centrosome and activated, causing aberrant activation of centrosomal Akt and cyclin-dependent kinase 2 (CDK2)/cyclin A and leading to centrosome overduplication. Centrosome overduplication caused by SF-1 depletion was averted by the elimination of DNA-PKcs, Ku70/80, or cyclin A or by the inhibition of CDK2 or Akt. In the nucleus, SF-1 did not interact with Ku70/80, and SF-1 depletion did not activate a nuclear DNA damage response. Centriole biogenesis was also unaffected. Thus, centrosomal DNA-PK signaling triggers centrosome overduplication, and this centrosomal event, but not the nuclear DNA damage response, is controlled by SF-1.

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 The DNA Damage Response Kinases DNA-dependent Protein Kinase (DNA-PK) and Ataxia Telangiectasia Mutated (ATM) Are Stimulated by Bulky Adduct-containing DNA

2011 ◽  
Vol 286 (22) ◽  
pp. 19237-19246 ◽  
Author(s):  
Michael G. Kemp ◽  
Laura A. Lindsey-Boltz ◽  
Aziz Sancar
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Dna Adducts ◽  
Ataxia Telangiectasia ◽  
Ataxia Telangiectasia Mutated ◽  
Dependent Protein Kinase ◽  
Damage Response ◽  
Dependent Protein ◽  
Bulky Dna Adducts

A variety of environmental, carcinogenic, and chemotherapeutic agents form bulky lesions on DNA that activate DNA damage checkpoint signaling pathways in human cells. To identify the mechanisms by which bulky DNA adducts induce damage signaling, we developed an in vitro assay using mammalian cell nuclear extract and plasmid DNA containing bulky adducts formed by N-acetoxy-2-acetylaminofluorene or benzo(a)pyrene diol epoxide. Using this cell-free system together with a variety of pharmacological, genetic, and biochemical approaches, we identified the DNA damage response kinases DNA-dependent protein kinase (DNA-PK) and ataxia telangiectasia mutated (ATM) as bulky DNA damage-stimulated kinases that phosphorylate physiologically important residues on the checkpoint proteins p53, Chk1, and RPA. Consistent with these results, purified DNA-PK and ATM were directly stimulated by bulky adduct-containing DNA and preferentially associated with damaged DNA in vitro. Because the DNA damage response kinase ATM and Rad3-related (ATR) is also stimulated by bulky DNA adducts, we conclude that a common biochemical mechanism exists for activation of DNA-PK, ATM, and ATR by bulky adduct-containing DNA.

Sign in / Sign up

Export Citation Format

Share Document