Foxo3 circular RNA retards cell cycle progression via forming ternary complexes with p21 and CDK2

TLDR

Non‑coding RNAs, including circular RNAs (circRNAs) and intronic ciRNAs, are abundant in the human genome; while ciRNAs can promote transcription, circRNAs’ functions remain largely unknown, though they may act as microRNA sponges. Circ‑Foxo3, highly expressed in non‑cancer cells, suppresses cell‑cycle progression by forming a ternary complex with CDK2 and p21 that blocks CDK2 activity, whereas its knockdown promotes proliferation.

Abstract

Most RNAs generated by the human genome have no protein-coding ability and are termed non-coding RNAs. Among these include circular RNAs, which include exonic circular RNAs (circRNA), mainly found in the cytoplasm, and intronic RNAs (ciRNA), predominantly detected in the nucleus. The biological functions of circular RNAs remain largely unknown, although ciRNAs have been reported to promote gene transcription, while circRNAs may function as microRNA sponges. We demonstrate that the circular RNA circ-Foxo3 was highly expressed in non-cancer cells and were associated with cell cycle progression. Silencing endogenous circ-Foxo3 promoted cell proliferation. Ectopic expression of circ-Foxo3 repressed cell cycle progression by binding to the cell cycle proteins cyclin-dependent kinase 2 (also known as cell division protein kinase 2 or CDK2) and cyclin-dependent kinase inhibitor 1 (or p21), resulting in the formation of a ternary complex. Normally, CDK2 interacts with cyclin A and cyclin E to facilitate cell cycle entry, while p21works to inhibit these interactions and arrest cell cycle progression. The formation of this circ-Foxo3-p21-CDK2 ternary complex arrested the function of CDK2 and blocked cell cycle progression.