ATRX loss inhibits DDR to strengthen radio-sensitization in p53-deficent HCT116 cells.

Identifying novel targets for molecular radiosensitization is critical for improving the efficacy of colorectal cancer (CRC) 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 and the regulation of apoptosis and senescence. However, whether ATRX is directly involved in the radiosensitivity of CRC remains unclear. Our results showed that silencing ATRX increased the radiosensitivity of HCT116 CRC cells, which was further strengthened when p53 was depleted. To explore the potential mechanism, we focused on the impact of the ionizing radiation (IR)-induced DNA damage response (DDR), apoptosis, and senescence and the activation of the Daxx/MDM2/p53 pathway caused by ATRX loss. The results showed that IR induced DNA damage and G2/M arrest after depleting ATRX, especially in p53-depleted HCT116 cells, and inhibited ATM/Chk2 pathway activation, indicating that ATRX loss leads to failure of triggering the ATM/Chk2 pathway. Accordingly, ATRX loss promotes cell apoptosis and attenuates cell senescence. Interestingly, our results indicate that ATRX loss upregulates p53 function via the Daxx/MDM2 pathway to mediate radiosensitivity. Thus, ATRX may represent a novel radiosensitizing target for CRC, particularly p53-deficient CRC.