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C11orf54 promotes DNA repair via blocking CMA-mediated degradation of HIF1A

Junyang Tan1,2, Wenjun Wang1,2, Xinjie Liu1,2

  • 1The Sixth Affiliated Hospital of Jinan University, Jinan University, 523573, Dongguan, Guangdong, China.

Communications Biology
|June 5, 2023
PubMed

Insights

C11orf54 protein knockdown impairs homologous recombination repair and DNA synthesis by reducing HIF1A and RRM2 levels via chaperone-mediated autophagy. This leads to increased DNA damage and cell death in cancer cells.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Biochemistry

Background:

  • C11orf54 is a conserved ester hydrolase and a potential biomarker for renal cancers.
  • The precise biological function of C11orf54 remains largely unelucidated.
  • Understanding C11orf54's role is crucial for cancer research and therapeutic development.

Purpose of the Study:

  • To investigate the functional role of C11orf54 in cellular processes.
  • To elucidate the molecular mechanisms underlying C11orf54's involvement in DNA damage and repair.
  • To explore the potential of targeting C11orf54 in cancer therapy.

Main Methods:

  • C11orf54 knockdown using RNA interference.
  • Assessment of cell proliferation, DNA damage, and apoptosis.
  • Analysis of homologous recombination repair (HRR) pathway proteins (e.g., Rad51).
  • Investigation of protein-protein interactions using co-immunoprecipitation.
  • Chaperone-mediated autophagy (CMA) pathway analysis.
  • Measurement of ribonucleotide reductase regulatory subunit M2 (RRM2) expression.
  • Supplementation experiments with deoxynucleotides (dNTPs) and Bafilomycin A1.

Main Results:

  • C11orf54 knockdown suppressed cell proliferation and enhanced cisplatin-induced DNA damage and apoptosis.
  • Loss of C11orf54 reduced Rad51 expression and nuclear accumulation, impairing homologous recombination repair.
  • C11orf54 knockdown promoted HSC70-mediated degradation of HIF1A via chaperone-mediated autophagy.
  • Reduced HIF1A levels led to decreased RRM2 transcription, impacting dNTP availability for DNA synthesis and repair.
  • Supplementation with dNTPs or Bafilomycin A1 partially rescued the DNA damage and cell death phenotypes.

Conclusions:

  • C11orf54 plays a significant role in regulating DNA damage and repair pathways.
  • The study uncovers a novel mechanism involving C11orf54, chaperone-mediated autophagy, HIF1A, and RRM2 in controlling DNA integrity.
  • These findings provide new insights into the function of C11orf54 and suggest potential therapeutic strategies targeting this axis in cancer.

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