alpha-Sarcin catalytic activity is not required for cytotoxicity

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dc.contributor.authorAlford, Spencer C.
dc.contributor.authorPearson, Joel D.
dc.contributor.authorCarette, Amanda
dc.contributor.authorIngham, Robert J.
dc.contributor.authorHoward, Perry L.
dc.date.accessioned2014-07-15T23:49:47Z
dc.date.available2014-07-15T23:49:47Z
dc.date.copyright2009en_US
dc.date.issued2009-04-03
dc.descriptionBioMd Centralen_US
dc.description.abstractBackground: α-Sarcin is a protein toxin produced by Aspergillus giganteus. It belongs to a family of cytotoxic ribonucleases that inactivate the ribosome and inhibit protein synthesis. α-Sarcin cleaves a single phosphodiester bond within the RNA backbone of the large ribosomal subunit, which makes the ribosome unrecognizable to elongation factors and, in turn, blocks protein synthesis. Although it is widely held that the protein synthesis inhibition caused by the toxin leads to cell death, it has not been directly shown that catalytically inactive mutants of α-sarcin are non-toxic when expressed directly within the cytoplasm of cells. This is important since recent studies have cast doubt on whether protein synthesis inhibition is sufficient to initiate apoptosis. Results: In this report, we assay α-sarcin cytotoxicity and ability to inhibit protein synthesis by direct cytoplasmic expression. We show that mutations in α-sarcin, which impair α-sarcin's ability to inhibit protein synthesis, do not affect its cytotoxicity. The mutants are unable to activate JNK, confirming that the sarcin-ricin loop remains intact and that the α-sarcin mutants are catalytically inactive. In addition, both mutant and wildtype variants of α-sarcin localize to the nucleus and cytoplasm, where they co-localize with ribosomal marker RPS6. Conclusion: We conclude that although protein synthesis inhibition likely contributes to cell death, it is not required. Thus, our results suggest that α-sarcin can promote cell death through a previously unappreciated mechanism that is independent of rRNA cleavage and JNK activation.en_US
dc.description.reviewstatusRevieweden_US
dc.description.scholarlevelFacultyen_US
dc.description.sponsorshipThis work was funded by an NSERC Discovery Grant (PLH)en_US
dc.identifier.citationAlford et al. Alpha-Sarcin catalytic activity is not required for cytotoxicity. BMC Biochemistry 2009 10:9.en_US
dc.identifier.urihttp://www.biomedcentral.com/1471-2091/10/9
dc.identifier.urihttp://dx.doi.org/10.1186/1471-2091-10-9
dc.identifier.urihttp://hdl.handle.net/1828/5459
dc.language.isoenen_US
dc.publisherBioMed Centralen_US
dc.subjectCentre for Biomedical Research
dc.subject.departmentDepartment of Biochemistry and Microbiology
dc.subject.departmentDepartment of Biology
dc.titlealpha-Sarcin catalytic activity is not required for cytotoxicityen_US
dc.typeArticleen_US

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