Show simple item record

dc.contributor.authorEngelward, Bevin P.
dc.contributor.authorRugo, Rebecca
dc.contributor.authorMutamba, James Tendai
dc.contributor.authorYee, Tiffany L.
dc.contributor.authorChaillet, J. R.
dc.contributor.authorGreenberger, Joel S.
dc.contributor.authorMohan, K. N.
dc.date.accessioned2010-12-17T16:08:04Z
dc.date.available2010-12-17T16:08:04Z
dc.date.issued2010-11
dc.date.submitted2008-09
dc.identifier.issn0950-9232
dc.identifier.issn1476-5594
dc.identifier.urihttp://hdl.handle.net/1721.1/60300
dc.description.abstractCharacterization of the direct effects of DNA-damaging agents shows how DNA lesions lead to specific mutations. Yet, serum from Hiroshima survivors, Chernobyl liquidators and radiotherapy patients can induce a clastogenic effect on naive cells, showing indirect induction of genomic instability that persists years after exposure. Such indirect effects are not restricted to ionizing radiation, as chemical genotoxins also induce heritable and transmissible genomic instability phenotypes. Although such indirect induction of genomic instability is well described, the underlying mechanism has remained enigmatic. Here, we show that mouse embryonic stem cells exposed to γ-radiation bear the effects of the insult for weeks. Specifically, conditioned media from the progeny of exposed cells can induce DNA damage and homologous recombination in naive cells. Notably, cells exposed to conditioned media also elicit a genome-destabilizing effect on their neighbouring cells, thus demonstrating transmission of genomic instability. Moreover, we show that the underlying basis for the memory of an insult is completely dependent on two of the major DNA cytosine methyltransferases, Dnmt1 and Dnmt3a. Targeted disruption of these genes in exposed cells completely eliminates transmission of genomic instability. Furthermore, transient inactivation of Dnmt1, using a tet-suppressible allele, clears the memory of the insult, thus protecting neighbouring cells from indirect induction of genomic instability. We have thus demonstrated that a single exposure can lead to long-term, genome-destabilizing effects that spread from cell to cell, and we provide a specific molecular mechanism for these persistent bystander effects. Collectively, our results impact the current understanding of risks from toxin exposures and suggest modes of intervention for suppressing genomic instability in people exposed to carcinogenic genotoxins.en_US
dc.description.sponsorshipNational Institutes of Health. (U.S.) (Grant RO1- CA83876-8)en_US
dc.description.sponsorshipNational Institutes of Health. (U.S.) (NIH/NIAID CMCR U19 AI068021)en_US
dc.description.sponsorshipUnited States. Dept. of Energy (DE-FG02- 05ER64053)en_US
dc.description.sponsorshipNational Institute of Environmental Health Sciences (P30-ES002109)en_US
dc.description.sponsorshipDuke Cancer Instituteen_US
dc.language.isoen_US
dc.publisherNature Publishing Groupen_US
dc.relation.isversionofhttp://dx.doi.org/10.1038/onc.2010.480en_US
dc.rightsAttribution-Noncommercial-Share Alike 3.0 Unporteden_US
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/3.0/en_US
dc.sourceHoward Silveren_US
dc.titleMethyltransferases mediate cell memory of a genotoxic insulten_US
dc.typeArticleen_US
dc.identifier.citationRugo, R. E. et al. “Methyltransferases mediate cell memory of a genotoxic insult.” Oncogene (2010): p.1–6en_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biological Engineeringen_US
dc.contributor.approverEngelward, Bevin
dc.contributor.mitauthorEngelward, Bevin P.
dc.contributor.mitauthorRugo, Rebecca
dc.contributor.mitauthorMutamba, James Tendai
dc.contributor.mitauthorYee, Tiffany L.
dc.relation.journalOncogeneen_US
dc.eprint.versionAuthor's final manuscript
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dspace.orderedauthorsRugo, R E; Mutamba, J T; Mohan, K N; Yee, T; Chaillet, J R; Greenberger, J S; Engelward, B Pen
mit.licenseOPEN_ACCESS_POLICYen_US


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record