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

Circular RNAs (circRNAs) are a class of noncoding RNAs that have been found to be involved in intervertebral disc degeneration (IVDD) progression, and N6-methyladenosine (m6A) broadly exists in circRNAs. Here, we identified circGPATCH2L with a low m6A methylation level to be upregulated in degenerative nucleus pulposus tissues. Mechanistically, as a protein decoy for tripartite motif containing 28 (TRIM28) within aa 402–452 region, circGPATCH2L abrogates the phosphorylation of TRIM28 and inhibits P53 degradation, which contributes to DNA damage accumulation and cellular apoptosis and leads to IVDD progression. Moreover, m6A-methylated circGPATCH2L is recognised and endoribonucleolytically cleaved by a YTHDF2-RPL10-RNase P/MRP complex to maintain the physiological state of nucleus pulposus cells. Thus, our data show the physiological significance of m6A modification in regulating circRNA abundance and provide a potentially effective therapeutic target for the treatment of IVDD.