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

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 nucle...

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Bibliographic Details
Published in:Cell biology international 2022-12, Vol.46 (12), p.2158-2172
Main Authors: Li, Zixuan, Zhou, Zhou, Tian, Shuaiyu, Zhang, Kailu, An, Gangli, Zhang, Yarui, Ma, Renyuxue, Sheng, Binjie, Wang, Tian, Yang, Hongying, Yang, Lin
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Ataxia telangiectasia
Ataxia telangiectasia mutated protein
Cdc2 protein
Cell proliferation
Cell Proliferation - genetics
Cyclin B1
Deoxyribonucleic acid
DNA
DNA Damage
DNA Repair
EGFR
Epidermal growth factor receptors
ErbB Receptors - genetics
ErbB Receptors - metabolism
Hematopoiesis
Hematopoietic Stem Cells
hematopoietic stem cells (HSCs)
Ionizing radiation
Mice
p53 Protein
Phosphorylation
Protein kinase C
Radiation
Radiation protection
Radiation, Ionizing
Radioresistance
RPRM
Stat3 protein
Stem cell transplantation
Stem cells
Tumor suppressor genes
Tumor Suppressor Protein p53 - metabolism
Tumors
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Summary: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.
ISSN:1065-6995
1095-8355
DOI:10.1002/cbin.11900