Loss of ATRX Sensitizes HeLa Cells in Response to Ionizing Irradiation in a Manner Dependent on the ATM/Chk2 Pathway

Abstract Background: Alpha-thalassemia/mental retardation X-linked (ATRX), a member of the SWI/SNF-like chromatin remodeling protein family, functions in the maintenance of genomic integrity, alternative lengthening of telomeres, and the regulation of apoptosis and senescence. However, whether ATRX is directly involved in the DNA damage response (DDR) remains unknown. Here, we Identify novel targets for molecular radiosensitization for cancer radiotherapy.Methods: ATRX-depleted HeLa cell lines were obtained by RNAi, after radiation, DNA damage repair were implied by γH2AX foci and expressions of γH2AX and Rad51. The survival fraction (SF), cell proliferation, cell apoptosis and cell senescence were measured to demonstrate the radiosensitization. In addition, IL-6, -8 and CXCL-1 mRNAs and apoptotic protein and cell cycle-regulated protein expressions were measured to analyze the molecular mechanisms. Results: IR-induced DNA damage was greater and G2/M arrest was less efficient in ATRX knockdown cells. ATRX downregulation caused defects in apoptosis and senescence, indicating that ATRX has a biological function in the DDR. ATRX loss led to failure to trigger ataxia telangiectasia-mutated (ATM) auto-phosphorylation, inhibiting the activation of ATM/Chk2 downstream effectors. Conclusions: These data identify ATRX as a novel target for radiosensitization, and its effect depends on inhibition of the ATM/Chk2 pathway in the DDR.