From circRNAs to fusion circRNAs in hematological malignancies
Loelia Babin, … , Erika Brunet, Fabienne Meggetto
Loelia Babin, … , Erika Brunet, Fabienne Meggetto
Published November 8, 2021
Citation Information: JCI Insight. 2021;6(21):e151513. https://doi.org/10.1172/jci.insight.151513.
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Review

From circRNAs to fusion circRNAs in hematological malignancies

Abstract

Circular RNAs (circRNAs) represent a type of endogenous noncoding RNA generated by back-splicing events. Unlike the majority of RNAs, circRNAs are covalently closed, without a 5′ end or a 3′ poly(A) tail. A few circRNAs can be associated with polysomes, suggesting a protein-coding potential. CircRNAs are not degraded by RNA exonucleases or ribonuclease R and are enriched in exosomes. Recent developments in experimental methods coupled with evolving bioinformatic approaches have accelerated functional investigation of circRNAs, which exhibit a stable structure, a long half-life, and tumor specificity and can be extracted from body fluids and used as potential biological markers for tumors. Moreover, circRNAs may regulate the occurrence and development of cancers and contribute to drug resistance through a variety of molecular mechanisms. Despite the identification of a growing number of circRNAs, their effects in hematological cancers remain largely unknown. Recent studies indicate that circRNAs could also originate from fusion genes (fusion circRNAs, f-circRNAs) next to chromosomal translocations, which are considered the primary cause of various cancers, notably hematological malignancies. This Review will focus on circRNAs and f-circRNAs in hematological cancers.

Authors

Loelia Babin, Elissa Andraos, Steffen Fuchs, Stéphane Pyronnet, Erika Brunet, Fabienne Meggetto

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Figure 1

CircRNA diversity and biogenesis.

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CircRNA diversity and biogenesis. (A) Pre-mRNA can be processed through ...
(A) Pre-mRNA can be processed through either canonical splicing to produce linear RNAs or back-splicing to generate circRNAs. CircRNAs are mainly divided into three categories based on their components: exonic circRNAs (EcircRNAs) are exclusively composed of exons and represent the largest group of circRNAs, intronic circRNAs (ciRNAs) are exclusively composed of introns, and exon-intron circRNAs (EIcircRNAs) are composed of exon-intron sequences. (B) A single gene locus can produce both linear and circular transcripts by canonical splicing or back-splicing mechanisms, respectively. (C) A single gene locus can produce multiple circRNAs that share the same back-splice site through a mechanism called alternative back-splicing (ABS), due to the competition among inverted complementary sequences across introns that bracket the circRNA-forming exons. There are two types of ABS events, alternative 5′ back-splicing (A5BS) and alternative 3′ back-splicing (A3BS). In an A5BS event, two or more downstream 5′ back-splice sites are alternatively joined with the same upstream 3′ back-splice site, while for A3BS circRNAs, the same downstream 5′ back-splice site is alternatively joined with two or more upstream 3′ back-splice sites. (D) Two main models have been proposed for circular RNA formation. Model 1: Lariat-driven circularization (exon skipping). Splice donor in the 3′ end of exon 2 covalently splices to the splice acceptor in the 5′ end of exon 3 and forms a lariat via exon skipping. Model 2: Intron-pairing-driven circularization. Intron 2 and intron 4 form a circular structure via base-pairing (-) or trans factors such as RNA-binding proteins (RBPs). The introns are then removed and EIcircRNA, EcircRNA, and intron lariat (ciRNA) are formed.