Noncoding RNAs in apoptosis: identification and function

Abstract

Apoptosis is a vital cellular process that is critical for the maintenance of homeostasis in health and disease. The derailment of apoptotic mechanisms has severe consequences such as abnormal development, cancer, and neurodegenerative diseases. Thus, there exist complex regulatory mechanisms in eukaryotes to preserve the balance between cell growth and cell death. Initially, protein-coding genes were prioritized in the search for such regulatory macromolecules involved in the regulation of apoptosis. However, recent genome annotations and transcriptomics studies have uncovered a plethora of regulatory noncoding RNAs that have the ability to modulate not only apoptosis but also many other biochemical processes in eukaryotes. In this review article, we will cover a brief summary of apoptosis and detection methods followed by an extensive discussion on microRNAs, circular RNAs, and long noncoding RNAs in apoptosis.

Keywords: Apoptosis; circular RNA; long noncoding RNA; microRNA; noncoding RNA.

Figure 1

Three pathways of apoptosis. The extrinsic signalling pathway is initiated through the binding of a ligand to transmembrane receptors. The death domain plays a critical role in transmitting the death signal from the cell surface into the cell through caspase-8. External stimuli such as cell stress, hypoxia, and radiation trigger the intrinsic pathway that causes cytochrome-c release from mitochondria. Cytotoxic T-cells are the main controllers for the granzyme pathway, which results in caspase-10 activation. Granzyme B can activate caspases in the targeted cell.

Figure 2

microRNA biogenesis and mode of actions. (A) Canonical and non-canonical pathways of microRNA biogenesis. In the canonical pathway, hairpin structured pri-microRNAs are converted into ~70–80 nucleotide precursor microRNAs (pre-microRNAs) by the RNase III enzyme Drosha in the nucleus. Pre-microRNAs are exported from the nucleus to the cytoplasm by Exportin-5. Dicer-processed mature microRNAs are incorporated into a microribonucleoprotein complex (miRISC complex). Non-canonical miRNA biogenesis does not involve Drosha. (B) Localization of miRISCs. miRISCs can be localized in (1) rough endoplasmic reticulum, (2) Golgi, (3) mitochondria, (4) vesicles, (5) free polysomes, and (6) cytoskeleton-bound polysomes. (C) Possible mechanisms for miRNA-mediated gene regulation. Binding of a miRNA to its target mRNA triggers either mRNA decay/cleavage or inhibition of translation.

Figure 3

Schematic representation of circRNA biogenesis and mode of actions. (A) Two proposed models of circRNA formation. In lariat-driven circRNA biogenesis, exon-skipping leads to an alternative form of linear RNA and a lariat, which undergoes back-splicing to form a circRNA. In direct backsplicing circRNA biogenesis, flanking inverted repeats or trans-acting factor-mediated base pairing facilitates circRNA production. (B) Five modes of action of circRNAs: (1) circRNAs can promote parental gene transcription by interacting with RNA Pol II, (2) circRNAs might undergo m6A-mediated cap-independent translation, (3) circRNAs might encode unique peptides, (4) circRNAs can interact with proteins and modulate their functions, (5) circRNAs can serve as miRNA sponges to regulate the fate of target mRNA.

Figure 4

lncRNA classification and mode of action. (A) lncRNA classification. lncRNAs are classified, based on their genomic position, as intergenic, intronic, antisense, bidirectional and enhancer RNA. Intergenic lncRNAs are localized between two protein coding genes and transcribed from intergenic regions, while intronic lncRNAs are processed from introns of protein coding genes. Antisense lncRNAs are transcribed from the complementary strand of a protein coding gene. Bidirectional lncRNAs are transcribed from both stands, and enhancer RNAs are transcribed from enhancer regions. (B) lncRNA mode of action. lncRNAs act as molecular guides, scaffolds, signals, and decoys in cell. lncRNAs mediate the recruitment of chromatin modifiers to modulate gene expression of target gene expression and chromatin dynamics as molecular guides. lncRNAs can direct the assembly of protein complexes to target genes as molecular scaffolds. lncRNAs are transcribed as response to specific stimuli and work in a cooperation with transcription factors to regulate transcription of downstream genes as molecular signals. lncRNAs function as molecular decoys by blocking transcriptional regulators.