日本放射線影響学会大会講演要旨集
The 48th Annual Meeting of The Japan Radiation Research Society
セッションID: S7-5
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Molecular mechanisms associated with radiation induced DNA damage and repair
Oxidative damage-induced telomere attrition and genomic instability in DNA repair deficient mammalian cells
*M Prakash HANDELakshmi BALAKRISHNANAnuradha POONEPALLIGrace KM LOWJennifer P NEWMANRohini KASHIMSHETTYAik Kia KHAWRabindranath BHATTACHARJEEShizuo AKIRAManikandan JAYAPALAdayabalam S BALAJEE
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Arsenite (As3+) has long been known to induce cancer and other degenerative diseases. Arsenite exerts its toxicity in part by generating reactive oxygen species. Identification of genetic factors that contribute to arsenic mutagenicity and carcinogenicity is critical for safeguarding the human population from arsenic exposure. As Poly (ADP-ribose) polymerase (PARP) is critical for genomic DNA stability, PARP-1 was evaluated in arsenic induced cytotoxic and genotoxic effects Our study revealed that telomere attrition, probably owing to arsenite-induced oxidative stress, was much more pronounced in PARP-1-/- MEFs (mouse embryonic fibroblasts) (40%) as compared to PARP-1+/+ MEFs (10-20%). Correlation observed between telomere reduction and apoptotic death in PARP-1 null cells strongly indicates that the telomere attrition might be a trigger for enhanced apoptotic death after arsenite treatment. Elevated DNA damage detected by alkaline comet assay points to an impaired repair ability of arsenite induced DNA lesions in PARP-1-/- MEFs. Consistent with elevated DNA damage, increased micronuclei induction reflecting gross genomic instability was also observed in arsenite treated PARP-1-/- MEFs. Microarray analysis has revealed that arsenite treatment altered the expression of about 311 genes of which a large fraction them have known functions in cellular responses to stress/external stimulus and cell growth and/or maintenance. Data obtained from other DNA repair deficient cells (such as cells lacking p53, DNA-PK, XPA) as well as telomerase negative mouse cells will be discussed.

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© 2005 The Japan Radiation Research Society
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