title: DNA damage signaling guards against perturbation of cyclin D1 expression triggered by low-dose long-term fractionated radiation.
abstract: Cyclin D1 expression is precisely controlled during cell-cycle progression. However, repeated exposure to low-dose fractionated radiation (FR) abrogates cell cycle-dependent cyclin D1 degradation by constitutive activation of AKT survival signaling in normal human fibroblasts. The resulting abnormal nuclear cyclin D1 accumulation induces defects in DNA replication and resulting DNA double-strand breaks, and is associated with induction of genomic instability in low-dose irradiated cells. Here, we investigated the role of DNA damage signaling against such perturbed cell-cycle control of cyclin D1 expression. Nuclear cyclin D1 accumulation was induced within 7 days after low-dose FR (0.01 Gy or 0.05 Gy per fraction) in ATM-deficient cells (AT5BIVA), but appeared later in AT5BIVA cells harboring human ATM cDNA. Thus, ATM prevents abnormal nuclear cyclin D1 accumulation at early time points after low-dose FR. We further demonstrated that ATM-mediated downregulation of protein phosphatase 2A activity caused activation of the AKT/cyclin D1 pathway after long-term FR. Perturbation of cyclin D1 expression induced Rad51 foci that indicate homologous recombination repair (HRR) in control cells, while ATM- and NBS1-deficient cells (GM7166) failed to induce Rad51 foci after long-term low-dose FR. After 21 days of FR, NBS1- and ATM-deficient cells showed a decrease in nuclear cyclin D1-positive cells, and an increase in apoptotic cells. Similarly, inhibition of ATM with KU55933 abrogated nuclear cyclin D1 accumulation by induction of apoptosis in ATM-complemented cells exposed to low-dose FR. In conclusion, we here demonstrate that ATM is involved in controlling cyclin D1 levels after low-dose FR. DNA damage signaling mitigates the harmful effects of low-dose long-term FR by suppression of cell death induced by perturbation of cyclin D1 expression.
authors.affiliation: Department of Environmental Health, National Institute of Public Health, Saitama, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Shimura
authors.affiliation: Department of Genome Dynamics, Radiation Biology Center, Kyoto University, Kyoto, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Kobayashi
authors.affiliation: Department of Genome Dynamics, Radiation Biology Center, Kyoto University, Kyoto, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Komatsu
authors.affiliation: Department of Environmental Health, National Institute of Public Health, Saitama, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Kunugita