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N6-methyladenosine hypomethylation of circGPATCH2L regulates DNA damage and apoptosis through TRIM28 in

Zhenhao Chen1, Jian Song1, Lin Xie2

  • 1Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai, 200000, China.

Cell Death and Differentiation
|July 12, 2023
PubMed

Insights

Circular RNAs (circRNAs) regulate intervertebral disc degeneration (IVDD). Low m6A methylation of circGPATCH2L promotes IVDD by inhibiting TRIM28 phosphorylation and P53 degradation, offering a therapeutic target.

Area of Science:

  • Molecular Biology
  • RNA Biology
  • Biochemistry

Background:

  • Circular RNAs (circRNAs) are implicated in intervertebral disc degeneration (IVDD).
  • N6-methyladenosine (m6A) modification is prevalent in circRNAs and influences their function.
  • Understanding circRNA regulation is crucial for addressing IVDD pathogenesis.

Purpose of the Study:

  • To investigate the role of circGPATCH2L, a circRNA with low m6A methylation, in IVDD.
  • To elucidate the molecular mechanism by which circGPATCH2L contributes to IVDD progression.
  • To explore the functional significance of m6A modification in regulating circRNA stability and function in nucleus pulposus cells.

Main Methods:

  • Identification and quantification of circGPATCH2L in degenerative nucleus pulposus tissues.
  • Investigation of circGPATCH2L's interaction with tripartite motif containing 28 (TRIM28) and its effect on TRIM28 phosphorylation and P53 degradation.
  • Analysis of the m6A-dependent regulation of circGPATCH2L stability by the YTHDF2-RPL10-RNase P/MRP complex.

Main Results:

  • circGPATCH2L was upregulated in degenerative nucleus pulposus tissues and exhibited low m6A methylation.
  • circGPATCH2L acts as a protein decoy for TRIM28, inhibiting its phosphorylation and leading to P53 accumulation, DNA damage, and apoptosis, thus promoting IVDD.
  • m6A-modified circGPATCH2L is cleaved by the YTHDF2-RPL10-RNase P/MRP complex, maintaining nucleus pulposus cell homeostasis.

Conclusions:

  • circGPATCH2L with low m6A methylation exacerbates IVDD by disrupting protein homeostasis and promoting cellular damage.
  • m6A modification is critical for regulating circRNA abundance and maintaining the physiological state of nucleus pulposus cells.
  • circGPATCH2L and its m6A modification represent a potential therapeutic target for IVDD treatment.

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