CircRNA: functions and properties of a novel potential biomarker for cancer

Abstract

Circular RNAs, a novel class of endogenous noncoding RNAs, are characterized by their covalently closed loop structures without a 5' cap or a 3' Poly A tail. Although the mechanisms of circular RNAs' generation and function are not fully clear, recent research has shown that circular RNAs may function as potential molecular markers for disease diagnosis and treatment and play an important role in the initiation and progression of human diseases, especially in tumours. This review summarizes some information about categories, biogenesis, functions at the molecular level, properties of circular RNAs and the possibility of circular RNAs as biomarkers in cancers.

Keywords: Biomarker; Non-coding RNA; Tumour; circRNA; microRNA sponge.

Fig. 1

Biosynthesis of ecircRNA and EIciRNA. a Exon-skipping or lariat-driven circularisation. First, a pre-mRNA is spliced, causing the 3′-hydroxyl of the upstream exon to covalently bond to the 5′-phosphate of the downstream exon. At the same time, the sequence between the exons becomes an RNA lariat containing several exons and introns. Second, in the RNA lariat, the 2′-hydroxyl of the 5′-intron reacts with the 5′-phosphate of the 3′-intron, followed by the 3′-hydroxyl of the 3′-exon reacting with the 5′-phosphate of the 5′-exon. As a result, an RNA double lariat and a circular RNA are produced. Finally, some introns of the circular RNA are removed, producing an ecircRNA or EIcirRNA. b. Direct back-splicing or intron-pairing-driven circularisation. First, the upstream intron pairs with the downstream intron. Second, the 2′-hydroxyl of the upstream intron reacts with the 5′-phosphate of the downstream intron, followed by the 3′-hydroxyl of the 3′-exon reacting with the 5′-phosphate of the 5′-exon. Thus, a circular RNA is produced. Finally, some introns of the circular RNA are removed, producing an ecircRNA or EIcirRNA. c. RNA-binding-protein-driven circularisation. First, RNA binding proteins (RBPs) bind the upstream and downstream introns. Second, the RBPs are attracted to each other, and form a bridge between the introns. Third, the 2′-hydroxyl of the upstream intron reacts with the 5′-phosphate of the downstream intron, followed by the 3′-hydroxyl of the 3′-exon reacting with the 5′-phosphate of the 5′-exon. Thus, a circular RNA is produced. Finally, some introns of the circular RNA are removed, producing an ecircRNA or EIcirRNA

Fig 2

Biosynthesis of circular RNAs from introns. a. Circular RNA from group I introns. First, an exogenous guanosine(G) attacks the 5′-terminus of the intron as nucleophile. The 5′-exon is cut off due to the transesterification. Second, the 3′-hydroxyl of the free exon attacks the 5′-terminus of the 3′-exon as nucleophile, producing a linear intron. Third, a 2′-hydroxyl close to the 3′-terminus of the linear intron attacks a phosphodiester bond close to the 5′-terminus, producing an RNA lariat circularized with 2′,5′-phosphodiester and releasing the 5′-terminal sequence. Finally, the 3′- tail of the RNA lariat is removed. b. Circular RNA from group II introns. First, the RNA precursor releases the 3′-exon. Finally, the 2′-hydroxyl of the 3′-terminus attacks the 5′-terminus of the intron, producing an circular RNA circularized with 2′,5′-phosphodiester. c. Circular intron RNA(ciRNA). First, a pre-mRNA is spliced by a spliceosome, producing an RNA lariat circularized with 2′,5′-phosphodiester. Finally, the 3′- tail of the RNA lariat is removed