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.

EGFR confers radioresistance in human oropharyngeal carcinoma by activating endoplasmic reticulum stress signaling PERK‐eIF2α‐GRP94 and IRE1α‐XBP1‐GRP78

“…Moreover, EGFR‐targeted therapy increased the radiosensitivity of non‐small cell lung cancer by inhibiting DSB repair . ATM is a critical protein that senses radiation‐induced DNA damage, gets phosphorylated, and activates downstream target proteins that inhibit cell cycle progression until completion of DNA repair or initiation of apoptosis . Our previous studies showed that ATM phosphorylation induced G2/M phase arrest in lymphoma cells and increased their radiosensitivity .…”

Severe mitochondrial damage associated with low-dose radiation sensitivity in ATM- and NBS1-deficient cells

“…As we previously reported, low-dose, long-term FR induces growth retardation in all 4 cell lines used in this article. 16 However, continuous treatment with NAC during FR rescued cell proliferation in all 4 cell lines ( Fig. S1).…”

“…We previously reported that lowdose, long-term FR induced apoptosis in all 4 cell lines. 16 As assessed by staining for annexin V, 47.1% of ATM-deficient 31FR cells were apoptotic, whereas 16.2% of ATM-complemented 31FR cells were apoptotic ( Fig. 5B).…”

Genetic network profiles associated with established resistance to ionizing radiation in acute promyelocytic leukemia cells and their extracellular vesicles

“…On the contrary, the downregulation of CCND1, which encodes cyclin D1 and affects DNA replication and cell proliferation, was an unexpected phenomenon (5,8,20). Shimura et al recently reported that repeated exposure to low-dose fractionated radiation abrogates cell cycle-dependent cyclin D1 degradation via the constitutive activation of AkT survival signaling in normal human fibroblasts (21). High-and low-dose radiation rates may induce different behaviors of some CCND1 gene regulators.…”