ABSTRACT
Circular RNAs (circRNAs) are covalently closed single-stranded RNA molecules derived from exons by alternative mRNA splicing. Circularization of single-stranded RNA molecules was already described in 1976 for viroids in plants. Since then several additional types of circular RNAs in many species have been described such as the circular single-stranded RNA genome of the hepatitis delta virus (HDV) or circular RNAs as products or intermediates of tRNA and rRNA maturation in archaea. CircRNAs are generally formed by covalent binding of the 5' site of an upstream exon with the 3' of the same or a downstream exon. Meanwhile, two different models of circRNA biogenesis have been described, the lariat or exon skipping model and the direct backsplicing model. In the lariat model, canonical splicing occurs before backsplicing, whereas in the direct backsplicing model, the circRNA is generated first. In this chapter, we will review the formation of circular RNAs and highlight the derivation of different types of circular RNAs.
Subject(s)
Alternative Splicing , RNA/genetics , Exons/genetics , Gene Expression Regulation , Humans , Introns/genetics , Models, Genetic , Nucleic Acid Conformation , RNA/metabolism , RNA, Bacterial/genetics , RNA, Bacterial/metabolism , RNA, Circular , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , RNA, Viral/genetics , RNA, Viral/metabolism , Spliceosomes/metabolism , Viroids/geneticsABSTRACT
Alternative mRNA splicing is a fundamental process to increase the versatility of the genome. In humans, cardiac mRNA splicing is involved in the pathophysiology of heart failure. Mutations in the splicing factor RNA binding motif protein 20 (RBM20) cause severe forms of cardiomyopathy. To identify novel cardiomyopathy-associated splicing factors, RNA-seq and tissue-enrichment analyses were performed, which identified up-regulated expression of Sam68-Like mammalian protein 2 (SLM2) in the left ventricle of dilated cardiomyopathy (DCM) patients. In the human heart, SLM2 binds to important transcripts of sarcomere constituents, such as those encoding myosin light chain 2 (MYL2), troponin I3 (TNNI3), troponin T2 (TNNT2), tropomyosin 1/2 (TPM1/2), and titin (TTN). Mechanistically, SLM2 mediates intron retention, prevents exon exclusion, and thereby mediates alternative splicing of the mRNA regions encoding the variable proline-, glutamate-, valine-, and lysine-rich (PEVK) domain and another part of the I-band region of titin. In summary, SLM2 is a novel cardiac splicing regulator with essential functions for maintaining cardiomyocyte integrity by binding to and processing the mRNAs of essential cardiac constituents such as titin.