RPRM negatively regulates ATM levels through its nuclear translocation on irradiation mediated by CDK4/6 and IPO11.

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.