dc.contributor.author | Liu, Xiaobo | |
dc.contributor.author | Andreescu, Silvana | |
dc.contributor.author | Takahashi, Noriko | |
dc.contributor.author | Gruber, Charley C | |
dc.contributor.author | Yang, Jason Hung-Ying | |
dc.contributor.author | Braff, Dana | |
dc.contributor.author | Yashaswini, Chittampalli N. | |
dc.contributor.author | Bhubhanil, Sakkarin | |
dc.contributor.author | Furuta, Yoshikazu | |
dc.contributor.author | Collins, James J. | |
dc.contributor.author | Walker, Graham C. | |
dc.date.accessioned | 2018-04-23T18:15:45Z | |
dc.date.available | 2018-04-23T18:15:45Z | |
dc.date.issued | 2017-08 | |
dc.date.submitted | 2017-05 | |
dc.identifier.issn | 0027-8424 | |
dc.identifier.issn | 1091-6490 | |
dc.identifier.uri | http://hdl.handle.net/1721.1/114885 | |
dc.description.abstract | Downstream metabolic events can contribute to the lethality of drugs or agents that interact with a primary cellular target. In bacteria, the production of reactive oxygen species (ROS) has been associated with the lethal effects of a variety of stresses including bactericidal antibiotics, but the relative contribution of this oxidative component to cell death depends on a variety of factors. Experimental evidence has suggested that unresolvable DNA problems caused by incorporation of oxidized nucleotides into nascent DNA followed by incomplete base excision repair contribute to the ROS-dependent component of antibiotic lethality. Expression of the chimeric periplasmic-cytoplasmic MalE-LacZ[subscript 72 – 47] protein is an historically important lethal stress originally identified during seminal genetic experiments that defined the SecY-dependent protein translocation system. Multiple, independent lines of evidence presented here indicate that the predominant mechanism for MalE-LacZ lethality shares attributes with the ROS-dependent component of antibiotic lethality. MalE-LacZ lethality requires molecular oxygen, and its expression induces ROS production. The increased susceptibility of mutants sensitive to oxidative stress to MalE-LacZ lethality indicates that ROS contribute causally to cell death rather than simply being produced by dying cells. Observations that support the proposed mechanism of cell death include MalE-LacZ expression being bacteriostatic rather than bactericidal in cells that over-express MutT, a nucleotide sanitizer that hydrolyzes 8-oxo-dGTP to the monophosphate, or that lack MutM and MutY, DNA glycosylases that process base pairs involving 8-oxo-dGTP. Our studies suggest stress-induced physiological changes that favor this mode of ROS-dependent death. | en_US |
dc.description.sponsorship | National Institutes of Health (U.S.) (Grant R01CA021615) | en_US |
dc.description.sponsorship | Defense Threat Reduction Agency (DTRA) (Grant HDTRA1-15-1-0051) | en_US |
dc.description.sponsorship | National Science Foundation (U.S.) (Grant 1336493) | en_US |
dc.description.sponsorship | National Institutes of Health (U.S.) (Grant K99GM118907) | en_US |
dc.publisher | National Academy of Sciences (U.S.) | en_US |
dc.relation.isversionof | http://dx.doi.org/10.1073/PNAS.1707466114 | en_US |
dc.rights | Article 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.source | National Academy of Sciences | en_US |
dc.title | Lethality of MalE-LacZ hybrid protein shares mechanistic attributes with oxidative component of antibiotic lethality | en_US |
dc.type | Article | en_US |
dc.identifier.citation | Takahashi, Noriko et al. “Lethality of MalE-LacZ Hybrid Protein Shares Mechanistic Attributes with Oxidative Component of Antibiotic Lethality.” Proceedings of the National Academy of Sciences 114, 34 (August 2017): 9164–9169 © 2017 National Academy of Sciences | en_US |
dc.contributor.department | Massachusetts Institute of Technology. Institute for Medical Engineering & Science | en_US |
dc.contributor.department | Massachusetts Institute of Technology. Department of Biological Engineering | en_US |
dc.contributor.department | Massachusetts Institute of Technology. Department of Biology | en_US |
dc.contributor.mitauthor | Takahashi, Noriko | |
dc.contributor.mitauthor | Gruber, Charley C | |
dc.contributor.mitauthor | Yang, Jason Hung-Ying | |
dc.contributor.mitauthor | Braff, Dana | |
dc.contributor.mitauthor | Yashaswini, Chittampalli N. | |
dc.contributor.mitauthor | Bhubhanil, Sakkarin | |
dc.contributor.mitauthor | Furuta, Yoshikazu | |
dc.contributor.mitauthor | Collins, James J. | |
dc.contributor.mitauthor | Walker, Graham C | |
dc.relation.journal | Proceedings of the National Academy of Sciences | en_US |
dc.eprint.version | Final published version | en_US |
dc.type.uri | http://purl.org/eprint/type/ConferencePaper | en_US |
eprint.status | http://purl.org/eprint/status/NonPeerReviewed | en_US |
dc.date.updated | 2018-04-20T13:43:59Z | |
dspace.orderedauthors | Takahashi, Noriko; Gruber, Charley C.; Yang, Jason H.; Liu, Xiaobo; Braff, Dana; Yashaswini, Chittampalli N.; Bhubhanil, Sakkarin; Furuta, Yoshikazu; Andreescu, Silvana; Collins, James J.; Walker, Graham C. | en_US |
dspace.embargo.terms | N | en_US |
dc.identifier.orcid | https://orcid.org/0000-0002-7127-9833 | |
dc.identifier.orcid | https://orcid.org/0000-0003-0921-4657 | |
dc.identifier.orcid | https://orcid.org/0000-0003-4710-1389 | |
dc.identifier.orcid | https://orcid.org/0000-0002-5560-8246 | |
dc.identifier.orcid | https://orcid.org/0000-0001-7243-8261 | |
mit.license | PUBLISHER_POLICY | en_US |