Loss of ATRX sensitizes HeLa cells in response to ionizing irradiation in a manner dependent on the ATM/Chk2 pathway
Identifying novel targets for molecular radiosensitization is critical to improve the efficacy of cancer radiotherapy. 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 show that silencing ATRX increased the sensitivity of cells to ionizing radiation (IR). 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. These data identify ATRX as a novel target for radiosensitization, and its effect depends on inhibition of the ATM/Chk2 pathway in the DDR.
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Posted 21 Aug, 2020
Loss of ATRX sensitizes HeLa cells in response to ionizing irradiation in a manner dependent on the ATM/Chk2 pathway
Posted 21 Aug, 2020
Identifying novel targets for molecular radiosensitization is critical to improve the efficacy of cancer radiotherapy. 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 show that silencing ATRX increased the sensitivity of cells to ionizing radiation (IR). 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. These data identify ATRX as a novel target for radiosensitization, and its effect depends on inhibition of the ATM/Chk2 pathway in the DDR.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6