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dc.contributor.authorRai, Prashant
dc.contributor.authorTay, Ian Jun Jie
dc.contributor.authorLi, Na
dc.contributor.authorAckerman, Shelley
dc.contributor.authorHe, Fang
dc.contributor.authorKwang, Jimmy
dc.contributor.authorChow, Vincent T.
dc.contributor.authorEngelward, Bevin P.
dc.contributor.authorParrish, Marcus Curtis
dc.contributor.authorTay, Jun Jie Ian
dc.date.accessioned2016-01-11T00:47:43Z
dc.date.available2016-01-11T00:47:43Z
dc.date.issued2015-06
dc.date.submitted2014-12
dc.identifier.issn0027-8424
dc.identifier.issn1091-6490
dc.identifier.urihttp://hdl.handle.net/1721.1/100789
dc.description.abstractStreptococcus pneumoniae is a leading cause of pneumonia and one of the most common causes of death globally. The impact of S. pneumoniae on host molecular processes that lead to detrimental pulmonary consequences is not fully understood. Here, we show that S. pneumoniae induces toxic DNA double-strand breaks (DSBs) in human alveolar epithelial cells, as indicated by ataxia telangiectasia mutated kinase (ATM)-dependent phosphorylation of histone H2AX and colocalization with p53-binding protein (53BP1). Furthermore, results show that DNA damage occurs in a bacterial contact-independent fashion and that Streptococcus pyruvate oxidase (SpxB), which enables synthesis of H[subscript 2]O[subscript 2], plays a critical role in inducing DSBs. The extent of DNA damage correlates with the extent of apoptosis, and DNA damage precedes apoptosis, which is consistent with the time required for execution of apoptosis. Furthermore, addition of catalase, which neutralizes H[subscript 2]O[subscript 2], greatly suppresses S. pneumoniae-induced DNA damage and apoptosis. Importantly, S. pneumoniae induces DSBs in the lungs of animals with acute pneumonia, and H[subscript 2]O[subscript 2] production by S. pneumoniae in vivo contributes to its genotoxicity and virulence. One of the major DSBs repair pathways is nonhomologous end joining for which Ku70/80 is essential for repair. We find that deficiency of Ku80 causes an increase in the levels of DSBs and apoptosis, underscoring the importance of DNA repair in preventing S. pneumoniae-induced genotoxicity. Taken together, this study shows that S. pneumoniae-induced damage to the host cell genome exacerbates its toxicity and pathogenesis, making DNA repair a potentially important susceptibility factor in people who suffer from pneumonia.en_US
dc.language.isoen_US
dc.publisherNational Academy of Sciences (U.S.)en_US
dc.relation.isversionofhttp://dx.doi.org/10.1073/pnas.1424144112en_US
dc.rightsArticle is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.en_US
dc.sourceNational Academy of Sciences (U.S.)en_US
dc.titleStreptococcus Pneumoniae Secretes Hydrogen Peroxide Leading to DNA Damage and Apoptosis in Lung Cellsen_US
dc.typeArticleen_US
dc.identifier.citationRai, Prashant, Marcus Parrish, Ian Jun Jie Tay, Na Li, Shelley Ackerman, Fang He, Jimmy Kwang, Vincent T. Chow, and Bevin P. Engelward. “ Streptococcus Pneumoniae Secretes Hydrogen Peroxide Leading to DNA Damage and Apoptosis in Lung Cells .” Proc Natl Acad Sci USA 112, no. 26 (June 15, 2015): E3421–E3430.en_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biological Engineeringen_US
dc.contributor.mitauthorParrish, Marcus Curtisen_US
dc.contributor.mitauthorTay, Jun Jie Ianen_US
dc.contributor.mitauthorAckerman, Shelleyen_US
dc.contributor.mitauthorEngelward, Bevin P.en_US
dc.relation.journalProceedings of the National Academy of Sciencesen_US
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dspace.orderedauthorsRai, Prashant; Parrish, Marcus; Tay, Ian Jun Jie; Li, Na; Ackerman, Shelley; He, Fang; Kwang, Jimmy; Chow, Vincent T.; Engelward, Bevin P.en_US
dc.identifier.orcidhttps://orcid.org/0000-0002-5472-3621
dc.identifier.orcidhttps://orcid.org/0000-0002-7149-9369
mit.licensePUBLISHER_POLICYen_US


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