A novel protein encoded by circARHGAP12 attenuates DNA damage and apoptosis by regulating MDC1 in intestinal ischemia/reperfusion injury

• Published in: International journal of biological macromolecules 2025-01, Vol.286, p.138374, Article 138374
• Main Authors: Liu, Deshun, Zhao, Xuzi, Wang, Zhecheng, Wang, Guangzhi, Chen, Zhao, Ning, Shili, Feng, Dongcheng, Sun, Xin, Sun, Ruimin, Yao, Jihong, Tian, Xiaofeng
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Apoptosis - genetics; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Circular RNA (circRNA); DNA Damage; Gene Expression Regulation; GTPase-Activating Proteins - genetics; GTPase-Activating Proteins - metabolism; Humans; Intestinal ischemia/reperfusion (I/R); Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; Intestines - pathology; Male; Mice; Protein coding; Reperfusion Injury - genetics; Reperfusion Injury - metabolism; Reperfusion Injury - pathology; RNA, Circular - genetics; RNA, Circular - metabolism
• ISSN: 0141-8130; 1879-0003; 1879-0003
• DOI: 10.1016/j.ijbiomac.2024.138374

Excessive intestinal ischemia/reperfusion (I/R)-induced epithelial cell apoptosis results in damage to the intestinal defense barrier. Circular RNAs (circRNAs) are functional RNA transcripts, and their functions as microRNA (miRNA) sponges and binding proteins have been well characterized. Recent evidence has indicated that some circRNAs encode functional proteins. However, whether protein-encoding circRNAs contribute to intestinal I/R remains undiscovered. Here, we identified a protein-encoding circRNA, circARHGAP12, that can significantly attenuate intestinal I/R-induced cell apoptosis. Moreover, circARHGAP12 can encode a 229-amino-acid (aa) protein, ARHGAP12-229aa. The expression of both circARHGAP12 and ARHGAP12-229aa was downregulated in intestinal I/R injury. Additionally, circARHGAP12 protected against intestinal I/R injury mainly by encoding ARHGAP12-229aa. We performed RNA sequencing (RNA-seq) analyses to identify downstream targets of ARHGAP12-229aa. The results revealed that overexpression of ARHGAP12-229aa led to increased expression of MDC1, a DNA damage-related protein, and that this increase was accompanied by a decrease in intestinal epithelial cell DNA damage and apoptosis. Furthermore, MDC1 silencing weakened the protective effect of ARHGAP12-229aa against intestinal I/R injury. Our findings suggest a novel perspective on circRNA function, providing an innovative therapeutic strategy for intestinal I/R.