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Title: Pneumococcal Pneumolysin Induces DNA Damage and Cell Cycle Arrest
Authors: Rai P.
He F.
Kwang J. 
Engelward B.P.
Chow V.T.K. 
Keywords: ATM protein
bacterial protein
DNA dependent protein kinase
H2AFX protein, human
MDC1 protein, human
nuclear protein
plY protein, Streptococcus pneumoniae
PRKDC protein, human
recombinant protein
TP53BP1 protein, human
transactivator protein
tumor suppressor p53 binding protein 1
A-549 cell line
cell cycle checkpoint
confocal microscopy
DNA damage
double stranded DNA break
drug effects
Streptococcus pneumoniae
Western blotting
A549 Cells
Ataxia Telangiectasia Mutated Proteins
Bacterial Proteins
Blotting, Western
Cell Cycle Checkpoints
DNA Breaks, Double-Stranded
DNA Damage
DNA-Activated Protein Kinase
Microscopy, Confocal
Nuclear Proteins
Recombinant Proteins
Streptococcus pneumoniae
Tumor Suppressor p53-Binding Protein 1
Issue Date: 2016
Publisher: Nature Publishing Group
Citation: Rai P., He F., Kwang J., Engelward B.P., Chow V.T.K. (2016). Pneumococcal Pneumolysin Induces DNA Damage and Cell Cycle Arrest. Scientific Reports 6 : 22972. ScholarBank@NUS Repository.
Abstract: Streptococcus pneumoniae produces pneumolysin toxin as a key virulence factor against host cells. Pneumolysin is a cholesterol-dependent cytolysin (CDC) toxin that forms lytic pores in host membranes and mediates pneumococcal disease pathogenesis by modulating inflammatory responses. Here, we show that pneumolysin, which is released during bacterial lysis, induces DNA double strand breaks (DSBs), as indicated by ataxia telangiectasia mutated (ATM)-mediated H2AX phosphorylation (?H2AX). Pneumolysin-induced ?H2AX foci recruit mediator of DNA damage checkpoint 1 (MDC1) and p53 binding protein 1 (53BP1), to sites of DSBs. Importantly, results show that toxin-induced DNA damage precedes cell cycle arrest and causes apoptosis when DNA-dependent protein kinase (DNA-PK)-mediated non-homologous end joining is inhibited. Further, we observe that cells that were undergoing DNA replication harbored DSBs in greater frequency during pneumolysin treatment. This observation raises the possibility that DSBs might be arising as a result of replication fork breakdown. Additionally, neutralizing the oligomerization domain of pneumolysin with monoclonal antibody suppresses DNA damage and also cell cycle arrest, indicating that pneumolysin oligomerization is important for causing DNA damage. Taken together, this study reveals a previously unidentified ability of pneumolysin to induce cytotoxicity via DNA damage, with implications in the pathophysiology of S. pneumoniae infection.
Source Title: Scientific Reports
ISSN: 20452322
DOI: 10.1038/srep22972
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