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

Abstract

Reprimo (RPRM), a target gene of p53, is a known tumor suppressor. DNA damage induces RPRM, which triggers p53-dependent G2 arrest by inhibiting cyclin B1/Cdc2 complex activation and promotes DNA damage-induced apoptosis. RPRM negatively regulates ataxia-telangiectasia mutated by promoting its nuclear-cytoplasmic translocation and degradation, thus inhibiting DNA damage. Therefore, RPRM plays a crucial role in DNA damage response. Moreover, the loss of RPRM confers radioresistance in mice, which enables longer survival and less severe intestinal injury after radiation exposure. However, the role of RPRM in radiation-induced hematopoietic system injury remains unknown. Herein, utilizing a RPRM-knockout mouse model, we found that RPRM deletion did not affect steady-state hematopoiesis in mice. However, RPRM knockout significantly alleviated radiation-induced hematopoietic system injury and preserved mouse hematopoietic regeneration in hematopoietic stem cells (HSCs) against radiation-induced DNA damage. Further mechanistic studies showed that RPRM loss significantly increased EGFR expression and phosphorylation in HSCs to activate STAT3 and DNA-PKcs, thus promoting HSC DNA repair and proliferation. These findings reveal the critical role of RPRM in radiation-induced hematopoietic system injury, confirming our hypothesis that RPRM may serve as a novel target for radiation protection.

Reprimo (RPRM) as a Potential Preventive and Therapeutic Target for Radiation-Induced Brain Injury via Multiple Mechanisms

“…We indeed observed a dramatically attenuated neurogenesis inhibition in RPRM KO mice after exposure to WBI (Figure 3). This is in accordance with what we found in the hematopoietic system, in which RPRM deletion preserved hematopoietic regeneration through promoting the DNA repair and proliferation of hematopoietic stem cell post IR [23]. All these data suggest that RPRM deletion may protect different types of brain cells against irradiation-induced damage.…”

“…We have recently discovered that RPRM indeed plays an important role in the DNA damage repair and radiosensitivity of cells through its negative regulatory effect on the ataxia-telangiectasia-mutated (ATM) protein kinase [22]. Thus, RPRM knockout significantly delays death in mice exposed to whole-body X-irradiation, and alleviates radiation-induced intestinal and hematopoietic system injury [22,23], suggesting that RPRM may play a crucial role in radiation-induced tissue injury. However, whether RPRM is involved in the occurrence of RIBI remains unknown.…”

Lineage plasticity and treatment resistance in prostate cancer: the intersection of genetics, epigenetics, and evolution

“…Moreover, wild-type p16 expression was consistent with radiosensitivity in malignant melanoma cells when compared to homozygous p16 deficient cell lines ( 147 ). The tumor suppressor RPRM has previously been implicated in triggering p53-mediated G2 cell cycle arrest following DNA damage ( 148 , 149 ) and negatively regulates ATM levels ( 150 ). Moreover, RPRM loss has been shown to confer radioresistance both in vitro and in vivo , marking RPRM as a potential target for cancer therapy and radiation protection ( 149 , 150 ).…”

“…The tumor suppressor RPRM has previously been implicated in triggering p53-mediated G2 cell cycle arrest following DNA damage ( 148 , 149 ) and negatively regulates ATM levels ( 150 ). Moreover, RPRM loss has been shown to confer radioresistance both in vitro and in vivo , marking RPRM as a potential target for cancer therapy and radiation protection ( 149 , 150 ). SFN is known to mediate G2 arrest by preventing the nuclear translocation of the CDC2-cyclin B1 complex in response to DNA damage ( 151 ).…”