RPRM negatively regulates ATM levels through its nuclear translocation on irradiation mediated by CDK4/6 and IPO11
Yarui Zhang,
Guomin Ou,
Zhujing Ye,
Zhou Zhou,
Qianlin Cao,
Mengting Li,
Jingdong Wang,
Jianping Cao,
Hongying Yang
Affiliations
Yarui Zhang
State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Suzhou Medical College of Soochow University/Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, 199 Renai Road, Suzhou Industrial Park, Suzhou, Jiangsu Province 215123, P. R. China
Guomin Ou
Department of Microbiology and Infectious Disease Center, School of Basic Medical Sciences, Peking University Health Science Center, 38 Xueyuan Road, Haidian District, Beijing 100191, P. R. China
Zhujing Ye
State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Suzhou Medical College of Soochow University/Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, 199 Renai Road, Suzhou Industrial Park, Suzhou, Jiangsu Province 215123, P. R. China
Zhou Zhou
State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Suzhou Medical College of Soochow University/Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, 199 Renai Road, Suzhou Industrial Park, Suzhou, Jiangsu Province 215123, P. R. China
Qianlin Cao
State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Suzhou Medical College of Soochow University/Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, 199 Renai Road, Suzhou Industrial Park, Suzhou, Jiangsu Province 215123, P. R. China
Mengting Li
State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Suzhou Medical College of Soochow University/Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, 199 Renai Road, Suzhou Industrial Park, Suzhou, Jiangsu Province 215123, P. R. China
Jingdong Wang
State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Suzhou Medical College of Soochow University/Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, 199 Renai Road, Suzhou Industrial Park, Suzhou, Jiangsu Province 215123, P. R. China
Jianping Cao
State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Suzhou Medical College of Soochow University/Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, 199 Renai Road, Suzhou Industrial Park, Suzhou, Jiangsu Province 215123, P. R. China
Hongying Yang
State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Suzhou Medical College of Soochow University/Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, 199 Renai Road, Suzhou Industrial Park, Suzhou, Jiangsu Province 215123, P. R. China; Corresponding author
Summary: How the ataxia telangiectasia mutated (ATM) protein kinase, a core protein in DNA damage response, is regulated at post-transcription level remains unclear. Here it is identified that protein Reprimo (RPRM) downregulates ATM protein levels, resulting in impaired DNA repair and enhanced cellular radiosensitivity. Mechanistically, although primarily localized in the cytoplasm, RPRM translocates to the nucleus shortly after induced by X-irradiation, interacts with ATM and promotes its nuclear export and proteasomal degradation. The RPRM nuclear translocation involves its phosphorylation at serine 98 mediated by cyclin-dependent kinases 4/6 (CDK4/6), and requires Importin-11 (IPO11). Of importance, IPO11-regulated RPRM nuclear import upon irradiation is essential for its regulation on ATM. Thus, RPRM overexpression and its phosphorylation inhibition sensitize cells to genotoxic agents such as irradiation, whereas RPRM deficiency significantly increases resistance to radiation-induced damage both in vitro and in vivo. These findings establish a crucial regulatory mechanism in which ATM is negatively modulated by RPRM.
