Aurora A Kinase Plays a Key Role in Mitosis Skip during Senescence Induced by Ionizing Radiation.

Xu Rui Zhang; Tong Shan Zhang; Ya Nan Zhang; Jun Rui Hua; Ju Fang Wang; Jin Peng HE

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Aurora A Kinase Plays a Key Role in Mitosis Skip during Senescence Induced by Ionizing Radiation.

Author: Xu Rui ZHANG ^{1
,

2} ; Tong Shan ZHANG ^{1
,

3} ; Ya Nan ZHANG ⁴ ; Jun Rui HUA ⁴ ; Ju Fang WANG ^{1
,

3} ; Jin Peng HE ^{1
,

3}
Author Information

1. Key Laboratory of Space Radiobiology of Gansu Province & CAS Key Laboratory of Heavy Ion Radiation Biology and Medicine, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, Gansu, China
2. National-Local Joint Engineering Research Center of Biodiagnostic & Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710004, Shaanxi, China.
3. University of Chinese Academy of Sciences, Beijing 100049, China.
4. Key Laboratory of Space Radiobiology of Gansu Province & CAS Key Laboratory of Heavy Ion Radiation Biology and Medicine, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou 730000, Gansu, China.
Publication Type:Journal Article
Keywords: G2 arrest; Ionizing radiation; Mitosis skipping; Senescence; Tetraploid
MeSH: Humans; Aurora Kinase A/metabolism*; Cell Line, Tumor; Mitosis; Cell Cycle; Radiation, Ionizing; RNA, Small Interfering/metabolism*; Cyclin-Dependent Kinase Inhibitor p21/metabolism*
From: Biomedical and Environmental Sciences 2023;36(10):903-916
CountryChina
Language:English
Abstract: OBJECTIVE:To investigate the fate and underlying mechanisms of G2 phase arrest in cancer cells elicited by ionizing radiation (IR).
METHODS:Human melanoma A375 and 92-1 cells were treated with X-rays radiation or Aurora A inhibitor MLN8237 (MLN) and/or p21 depletion by small interfering RNA (siRNA). Cell cycle distribution was determined using flow cytometry and a fluorescent ubiquitin-based cell cycle indicator (FUCCI) system combined with histone H3 phosphorylation at Ser10 (pS10 H3) detection. Senescence was assessed using senescence-associated-β-galactosidase (SA-β-Gal), Ki67, and γH2AX staining. Protein expression levels were determined using western blotting.
RESULTS:Tumor cells suffered severe DNA damage and underwent G2 arrest after IR treatment. The damaged cells did not successfully enter M phase nor were they stably blocked at G2 phase but underwent mitotic skipping and entered G1 phase as tetraploid cells, ultimately leading to senescence in G1. During this process, the p53/p21 pathway is hyperactivated. Accompanying p21 accumulation, Aurora A kinase levels declined sharply. MLN treatment confirmed that Aurora A kinase activity is essential for mitosis skipping and senescence induction.
CONCLUSION:Persistent p21 activation during IR-induced G2 phase blockade drives Aurora A kinase degradation, leading to senescence via mitotic skipping.