ATRX Knockdown Enhances Irradiation‐Induced Mitotic Catastrophe in p53‐Deficient Cancer Cells

Induction of mitotic catastrophe (MC), a tumor suppressor mechanism to maintain genomic stability, with exogenous agents is a promising therapeutic endpoint. During cell division, mitotic defects and DNA damage can lead to mitotic failure and eventual MC. Alpha‐thalassemia/mental retardation syndrome X‐linked (ATRX) play an important role in DNA replication and damage repair, in addition to enhancing sister chromatid cohesion to maintain mitosis. However, the effects of ATRX knockdown (KD) on irradiation‐induced MC and the underlying mechanism remain unclear. Therefore, the aim of the present study was to clarify the effects and mechanisms of ATRX KD on irradiation‐induced MC in p53‐wild type, p53‐deficient and p53‐mutant cancer cells. The results showed that irradiation induced G 2 /M phase arrest in three cells, while ATRX KD induced additional G 1 phase arrest and S phase delay in irradiated HCT116 p53 +/+ cells. Notably, ATRX KD induced typical characteristics of MC exclusively in p53‐deficient (HCT116 p53 −/− ) and p53‐mutant (MDA‐MB‐231) cells but not in p53‐proficient HCT116 counterparts. This effect was mechanistically linked to the downregulation of spindle assembly checkpoint (SAC) and chromosomal passenger complex (CPC) component proteins, which exacerbated irradiation‐induced MC and consequently enhanced radiation‐induced proliferation inhibition and apoptosis in HCT116 p53 −/− cells.