RPRM negatively regulates ATM levels involving its phosphorylation mediated by CDK4/CDK6

Abstract

Sensitizing cancer cells to radio- and chemotherapy remains a hot topic in cancer treatment. Here it is identified that Protein Reprimo (RPRM) negatively regulates the levels of ataxia-telangiectasia mutated (ATM) protein kinase, a master regulator of DNA damage response (DDR) in the presence of DNA double-strand breaks (DSBs), resulting in impaired DNA repair efficiency and enhanced cellular sensitivity to genotoxic agents. Mechanistically, although RPRM is primarily located in cytoplasm, it rapidly translocates to nucleus shortly after induced by X-irradiation, interacts with ATM and promotes the nuclear export and proteasomal degradation of ATM. The nuclear translocation of RPRM is associated with its phosphorylation at serine 98, which is mediated by cyclin-dependent kinases 4/6 (CDK4/6). Inhibition of CDK4/6 stabilizes RPRM and promotes its nuclear import, in turn enhances the nuclear export of ATM and the reduction of ATM levels. As a result, RPRM overexpression and its phosphorylation inhibition sensitize cells to genotoxic agents. Moreover, 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, suggesting that RPRM may serve as a novel target for both cancer therapy and radiation protection.

RPRM deletion preserves hematopoietic regeneration by promoting EGFR‐dependent DNA repair and hematopoietic stem cell proliferation post ionizing radiation

“…This suggested that RPRM deletion protected HSCs by promoting the NHEJ repair machinery. Along with our previous finding that RPRM negatively regulates ATM (Zhang et al, 2021), this result confirms the importance of RPRM in DDR. In addition to promoting DNA repair, RPRM deletion enhanced the self‐renewal and proliferation of HSCs, which also contributed to the protective effect of RPRM deletion on HSCs after exposure to irradiation.…”

“…RPRM expression can be induced by IR (Ohki et al, 2000; Zhang et al, 2021). Moreover, our previous results showed that RPRM‐knockout mice were more radioresistant and survived longer than WT mice after exposure to X‐ray irradiation (Zhang et al, 2021).…”

“…RPRM expression can be induced by IR (Ohki et al, 2000; Zhang et al, 2021). Moreover, our previous results showed that RPRM‐knockout mice were more radioresistant and survived longer than WT mice after exposure to X‐ray irradiation (Zhang et al, 2021). The hematopoietic systems of RPRM KO mice were thus analyzed at different time points following irradiation to explore the potential role of RPRM in radiation‐induced hematopoietic system injury.…”

“…Furthermore, we previously discovered that RPRM negatively regulates the ataxia-telangiectasia mutated (ATM) by promoting its nuclear-cytoplasmic translocation and degradation and inhibits DNA damage repair. Using an established RPRM-knockout mouse model, we also demonstrated that loss of RPRM confers radioresistance to mice which manifests as longer survival and less severe intestinal injury after radiation exposure, indicating that RPRM may be a potential target for radiation protection (Zhang et al, 2021). However, it remains unclear whether RPRM plays any role in radiation-induced hematopoietic syndrome and how it affects DNA repair in HSCs.…”

“…We have previously revealed that RPRM is a critical negative player in DNA damage repair (Zhang et al, 2021). Therefore, we explored whether RPRM knockout would affect DNA damage repair in the LSKs of mice after irradiation.…”