ATR signaling cooperates with ATM in the mechanism of low dose hypersensitivity induced by carbon ion beam

• Published in: DNA repair Vol. 34; pp. 1 - 8
• Main Authors: Xue, Lian, Furusawa, Yoshiya, Yu, Dong
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.10.2015
• Subjects: ataxia telangiectasia and Rad3 related; ataxia telangiectasia mutated homolog; Ataxia Telangiectasia Mutated Proteins - deficiency; Ataxia Telangiectasia Mutated Proteins - metabolism; ATM; ATR; Carbon; Cell Line; Cells, Cultured; checkpoint kinase 1; CHK1; DNA double strand break; DNA-dependent protein kinase catalytic subunit; DNA-PKcs; Dose-Response Relationship, Radiation; DSB; Early G2/M checkpoint; G2 Phase Cell Cycle Checkpoints; Heavy Ions; High LET; homologous recombination; HRS; Humans; hyper-radiosensitivity; induced radioresistance; ionizing radiation; IRR; LET; Linear Energy Transfer; Low dose hyper-radiosensitivity; NHEJ; non-homologous end-joining; Radiation Tolerance; replication protein A; RPA; Signal Transduction; single strand DNA; ssDNA; DNA-PKcs; RPA; Early G2/M checkpoint; HRS; IRR; IR; HR; DSB; Ionizing radiation; High LET; CHK1; LET; ATM; NHEJ; ssDNA; Low dose hyper-radiosensitivity; ATR; DNA double strand break; DNA-dependent protein kinase catalytic subunit; ataxia telangiectasia and Rad3 related; homologous recombination; ataxia telangiectasia mutated homolog; linear energy transfer; single strand DNA; hyper-radiosensitivity; replication protein A; checkpoint kinase 1; non-homologous end-joining; induced radioresistance
• ISSN: 1568-7864; 1568-7856; 1568-7856
• DOI: 10.1016/j.dnarep.2015.07.001

•The early G2/M checkpoint is an important factor for the low dose HRS response to heavy ions.•The early G2/M checkpoint can be observed in ATM deficient cells under low doses of heavy ion beams.•The ATR pathway plays a pivotal role in the early G2/M checkpoint of ATM-deficient cells following heavy ion radiation.•The ATR pathway was activated in a dose- and LET-dependent manner.•The ATR pathway cooperates with ATM in low dose hypersensitivity induced by carbon ion beam. Little work has been done on the mechanism of low dose hyper-radiosensitivity (HRS) and later appeared radioresistance (termed induced radioresistance (IRR)) after irradiation with medium and high linear energy transfer (LET) particles. The aim of this study was to find out whether ATR pathway is involved in the mechanism of HRS induced by high LET radiation. GM0639 cells and two ATM deficient/mutant cells, AT5BIVA and AT2KY were irradiated by carbon ion beam. Thymidine block technique was developed to enrich the G2-phase population. Radiation induced early G2/M checkpoint was quantitatively assess with dual-parameter flow cytometry by detecting the cells positive for phospho-histone H3. The involvement of ATR pathway in HRS/IRR response was detected with pretreatment of specific inhibitors prior to carbon ion beam. The link between the early G2/M checkpoint and HRS/IRR under carbon ion beam was first confirmed in GM0639 cells, through the enrichment of cell population in G2-phase or with Aurora kinase inhibitor that attenuates the transition from G2 to M phase. Interestingly, the early G2/M arrest could still be observed in ATM deficient/mutant cells with an effect of ATR signaling, which was discovered to function in an LET-dependent manner, even as low as 0.2Gy for carbon ion radiation. The involvement of ATR pathway in heavy particles induced HRS/IRR was determined with the specific ATR inhibitor in GM0639 cells, which affected the HRS/IRR occurrence similarly as ATM inhibitor. These data demonstrate that ATR pathway may cooperate with ATM in the mechanism of low dose hypersensitivity induced by carbon ion beam.