From circRNAs to fusion circRNAs in hematological malignancies
Loelia Babin, Elissa Andraos, Steffen Fuchs, Stéphane Pyronnet, Erika Brunet, Fabienne Meggetto
Loelia Babin, Elissa Andraos, Steffen Fuchs, Stéphane Pyronnet, Erika Brunet, Fabienne Meggetto
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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 2

CircRNA functions.

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CircRNA functions. (A) Splicing competitors between back-splicing for ci...
(A) Splicing competitors between back-splicing for circRNAs and canonical splicing for linear RNAs. Multiple circRNAs and linear RNAs can be generated from a single gene locus. Indeed, RNA pairing formed across flanking introns promotes back-splicing, leading to the formation of a circRNA and a linear RNA with exon exclusion, whereas RNA pairing formed within one individual intron promotes canonical splicing, inducing a linear RNA with exon exclusion but not back-splicing. Thus, the competition between these reverse complementary sequences can lead to multiple circRNAs. (B) Transcription regulators. CircRNAs can interact with RNA pol II, the complex containing U1 snRNP, and enhance gene transcription. CircRNAs can also silence genes by regulating parental genes through epigenetic mechanisms. (C) MiRNA sponges. CircRNAs can bind to miRNAs, thus inhibiting miRNA-mRNA conjugation. (D) Protein sponges. CircRNAs can restrain RBP from binding to miRNA or mRNA, thus indirectly regulating the protein biogenesis and the function of RBP. (E) Protein templates. CircRNAs can be translated into peptides when equipped with IRESs and AUG site(s). (F) Packaged into exosomes. Exo-circRNAs are circRNAs in exosomes where they can bind to miRNAs (top). After entering target cells, miRNAs are released and target genes can be silenced. In contrast, when exo-circRNAs are not bound to miRNAs in exosomes (bottom), they are able to sponge specific miRNAs in target cells and target genes are activated. U1, U1 small nuclear ribonucleoprotein particle (snRNP); RNA pol II, RNA polymerase II; RBP, RNA-binding protein; IRES, internal ribosome entry sites.