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Abstract
Manganese superoxide dismutase (SOD2) is a nuclear encoded and
mitochondria localized antioxidant enzyme that converts mitochondria derived
superoxide to hydrogen peroxide. This study investigates the hypothesis that
mitochondria derived reactive oxygen species (ROS) regulate ionizing radiation (IR)
induced transformation in normal cells. Mouse embryonic fibroblasts (MEFs) with wild
type SOD2 (+/+), heterozygous SOD2 (+/-), and homozygous SOD2 (-/-) genotypes
were irradiated with equitoxic doses of IR, and assayed for transformation frequency,
cellular redox environment, DNA damage, and cell cycle checkpoint activation.
Transformation frequency increased (~ 5-fold) in SOD2 (-/-) compared to SOD2 (+/+)
MEFs. Cellular redox environment (GSH, GSSG, DHE, and DCFH-oxidation) did not
show any significant change within 24h post-IR. However, a significant increase in
cellular ROS levels was observed at 72h post-IR in SOD2 (-/-) compared to SOD2 (+/+)
MEFs, which was consistent with an increase in GSSG in SOD2 (-/-) MEFs. Late ROS
accumulation was associated with an increase in micronuclei frequency in SOD2 (-/-)
MEFs. Exit from G2 was accelerated in irradiated SOD2 (+/-) and SOD2 (-/-) compared
to SOD2 (+/+) MEFs. These results support the hypothesis that SOD2 activity and
mitochondria generated ROS regulate IR induced transformation in mouse embryonic
fibroblasts.