Repair and removal of azoxymethane-induced O6-methylguanine in rat colon by O6-methylguanine DNA methyltransferase and apoptosis

dc.contributor.authorNyskohus, Laura S
dc.contributor.authorWatson, Amanda J
dc.contributor.authorMargison, Geoffrey P
dc.contributor.authorLe Leu, Richard Kevin
dc.contributor.authorKim, Susan Wonsun
dc.contributor.authorLockett, Trevor J
dc.contributor.authorHead, Richard J
dc.contributor.authorHu, Ying
dc.contributor.authorYoung, Graeme Paul
dc.date.accessioned2014-02-25T02:19:19Z
dc.date.available2014-02-25T02:19:19Z
dc.date.issued2013-12
dc.descriptionThis article appeared in a journal published by Elsevier. Under Elsevier's copyright, mandated authors are not permitted to make work available in an institutional repository.en
dc.description.abstractAzoxymethane (AOM) is an alkylating agent that generates mutagenic and carcinogenic O6-methylguanine (O6meG) adducts in DNA. O6meG has been detected in human colonic DNA; hence, understanding the innate cellular events occurring in response to the formation of O6meG is important in developing preventive strategies for colorectal cancer. We explored the time-course, dose–response, and kinetics of O6meG formation and its removal by the DNA repair protein, O6-methylguanine DNA methyltransferase (MGMT), and apoptosis. In rats given AOM (10 mg/kg), the formation of O6meG occurs within 2 h of exposure, accompanied by rapid depletion of MGMT activity and followed by the induction of an acute apoptotic response that peaks at 6–8 h. MGMT repair and apoptosis are dependent on AOM dose and O6meG load. Apoptosis is initiated only when a high O6meG load is present and MGMT activity is fully depleted. AOM, 10 mg/kg, overwhelms MGMT repair for about 96 h and renewed MGMT activity is only observed once O6meG is no longer detectable. A threshold for apoptosis is observed at 6 h after 6 mg/kg AOM, when a high O6meG persists and MGMT activity is very low. These data suggest that apoptosis is probably triggered by O6meG, but only once the capacity of MGMT to repair O6meG is exhausted. In the colonic epithelium, apoptosis may be complementary to MGMT, in terms of minimising potentially mutagenic events and maintaining a healthy genome.en
dc.description.sponsorshipThis study was supported in part by the CSIRO Preventative Health National Flagship Program, the Cancer Council of South Australia (CCSA 525925), the National Health and Medical Research Council (NHMRC 1007501), and Cancer Research UK.en
dc.identifier.citationNyskohus, L., Watson, A., Margison, G., Le Leu, R., Kim, S.W., Lockett, T., Head, R.J., Young, G.P., Hu, Y., (2013). Repair and removal of azoxymethane-induced O6-methylguanine in rat colon by O6-methylguanine DNA methyltransferase and apoptosis. Mutation Research-Genetic Toxicology and Environmental Mutagenesis, 758(1-2) pp. 80-86.en
dc.identifier.doihttps://doi.org/10.1016/j.mrgentox.2013.10.001en
dc.identifier.issn1383-5718
dc.identifier.urihttp://hdl.handle.net/2328/27469
dc.language.isoenen
dc.publisherElsevieren
dc.relationhttp://purl.org/au-research/grants/nhmrc/1007501en
dc.relation.grantnumberNHMRC/1007501en
dc.rights.holderElsevieren
dc.subjectAzoxymethaneen
dc.subjectDNA repairen
dc.subjectApoptosisen
dc.subjectColon canceren
dc.titleRepair and removal of azoxymethane-induced O6-methylguanine in rat colon by O6-methylguanine DNA methyltransferase and apoptosisen
dc.typeArticleen
local.contributor.authorOrcidLookupLe Leu, Richard Kevin: https://orcid.org/0000-0003-4704-4943en_US
local.contributor.authorOrcidLookupKim, Susan Wonsun: https://orcid.org/0000-0002-0924-8964en_US
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