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

Yarui Zhang1, Guomin Ou2, Zhujing Ye1

  • 1State 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.

Iscience
|October 3, 2022
PubMed

Insights

Protein Reprimo (RPRM) downregulates ataxia telangiectasia mutated (ATM) protein levels, impairing DNA repair and increasing radiosensitivity. RPRM nuclear import, regulated by Importin-11, is key to ATM degradation and cellular response to irradiation.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • The post-transcriptional regulation of ataxia telangiectasia mutated (ATM) protein kinase, crucial for DNA damage response, is not fully understood.
  • ATM protein kinase plays a central role in cellular responses to DNA damage, particularly double-strand breaks.

Purpose of the Study:

  • To elucidate the post-transcriptional regulatory mechanisms of ATM protein kinase.
  • To identify novel regulators of ATM protein levels and their impact on DNA repair and radiosensitivity.

Main Methods:

  • Investigated the interaction between Reprimo (RPRM) and ATM protein kinase using cell-based assays.
  • Utilized X-irradiation to induce DNA damage and observed RPRM translocation and ATM degradation.
  • Employed techniques like Western blotting, immunofluorescence, and co-immunoprecipitation to study protein interactions and localization.
  • Assessed cellular radiosensitivity and DNA repair capacity in cells with altered RPRM or Importin-11 (IPO11) expression.

Main Results:

  • Protein Reprimo (RPRM) was identified as a negative regulator of ATM protein levels.
  • RPRM translocates to the nucleus upon X-irradiation, interacts with ATM, and promotes its nuclear export and proteasomal degradation.
  • RPRM nuclear import is mediated by Importin-11 (IPO11) and phosphorylation at serine 98 by CDK4/6.
  • RPRM overexpression or IPO11 inhibition sensitizes cells to irradiation, while RPRM deficiency confers resistance to DNA damage.

Conclusions:

  • RPRM negatively modulates ATM protein levels through a mechanism involving nuclear import, interaction with ATM, and subsequent degradation.
  • The RPRM-ATM regulatory axis is critical for controlling cellular radiosensitivity and DNA repair efficiency.
  • Targeting the RPRM-IPO11 pathway offers potential strategies for enhancing cancer therapy sensitivity to genotoxic agents.
Keywords:
Cell biologyMolecular biology

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