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ATM-mediated DNA double-strand break response facilitated oncolytic Newcastle disease virus replication and promoted syncytium formation in tumor cells.
- Source :
-
PLoS pathogens [PLoS Pathog] 2020 Jun 01; Vol. 16 (6), pp. e1008514. Date of Electronic Publication: 2020 Jun 01 (Print Publication: 2020). - Publication Year :
- 2020
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Abstract
- Deoxyribonucleic acid (DNA) damage response (DDR) is the fundamental cellular response for maintaining genomic integrity and suppressing tumorigenesis. The activation of ataxia telangiectasia-mutated (ATM) kinase is central to DNA double-strand break (DSB) for maintaining host-genome integrity in mammalian cells. Oncolytic Newcastle disease virus (NDV) can selectively replicate in tumor cells; however, its influence on the genome integrity of tumor cells is not well-elucidated. Here, we found that membrane fusion and NDV infection triggered DSBs in tumor cells. The late replication and membrane fusion of NDV mechanistically activated the ATM-mediated DSB pathway via the ATM-Chk2 axis, as evidenced by the hallmarks of DSBs, i.e., auto-phosphorylated ATM and phosphorylated H2AX and Chk2. Immunofluorescence data showed that multifaceted ATM-controlled phosphorylation markedly induced the formation of pan-nuclear punctum foci in response to NDV infection and F-HN co-expression. Specific drug-inhibitory experiments on ATM kinase activity further suggested that ATM-mediated DSBs facilitated NDV replication and membrane fusion. We confirmed that the Mre11-RAD50-NBS1 (MRN) complex sensed the DSB signal activation triggered by NDV infection and membrane fusion. The pharmacological inhibition of MRN activity also significantly inhibited intracellular and extracellular NDV replication and syncytia formation. Collectively, these data identified for the first time a direct link between the membrane fusion induced by virus infection and DDR pathways, thereby providing new insights into the efficient replication of oncolytic NDV in tumor cells.<br />Competing Interests: All listed authors declare no competing financial interest.
- Subjects :
- A549 Cells
Acid Anhydride Hydrolases genetics
Acid Anhydride Hydrolases metabolism
Animals
Ataxia Telangiectasia Mutated Proteins genetics
Cell Cycle Proteins genetics
Cell Cycle Proteins metabolism
Chick Embryo
DNA-Binding Proteins genetics
DNA-Binding Proteins metabolism
HEK293 Cells
Humans
MRE11 Homologue Protein genetics
MRE11 Homologue Protein metabolism
Neoplasm Proteins genetics
Neoplasms genetics
Neoplasms virology
Nuclear Proteins genetics
Nuclear Proteins metabolism
Signal Transduction genetics
Ataxia Telangiectasia Mutated Proteins metabolism
DNA Breaks, Double-Stranded
Giant Cells metabolism
Giant Cells virology
Neoplasm Proteins metabolism
Neoplasms metabolism
Newcastle disease virus physiology
Oncolytic Viruses physiology
Virus Replication
Subjects
Details
- Language :
- English
- ISSN :
- 1553-7374
- Volume :
- 16
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- PLoS pathogens
- Publication Type :
- Academic Journal
- Accession number :
- 32479542
- Full Text :
- https://doi.org/10.1371/journal.ppat.1008514