Regulatory non-coding RNA: new instruments in the orchestration of cell death

Abstract

Non-coding RNA (ncRNA) comprises a substantial portion of primary transcripts that are generated by genomic transcription, but are not translated into protein. The possible functions of these once considered 'junk' molecules have incited considerable interest and new insights have emerged. The two major members of ncRNAs, namely micro RNA (miRNA) and long non-coding RNA (lncRNA), have important regulatory roles in gene expression and many important physiological processes, which has recently been extended to programmed cell death. The previous paradigm of programmed cell death only by apoptosis has recently expanded to include modalities of regulated necrosis (RN), and particularly necroptosis. However, most research efforts in this field have been on protein regulators, leaving the role of ncRNAs largely unexplored. In this review, we discuss important findings concerning miRNAs and lncRNAs that modulate apoptosis and RN pathways, as well as the miRNA-lncRNA interactions that affect cell death regulation.

Figure 1

The biological significance of ncRNAs. (a) ncRNAs comprise 99% of primary RNA transcripts generated by the genomic transcription. (b) ncRNAs comprise 80 to 90% of the poly-A-tailed mature RNAs. (c) Over 60% of the protein-coding genes in human are targets of miRNA. (d) About 70% of the protein-coding genes have at least one homologous antisense (as)-lncRNA

Figure 2

miRNAs that regulate cell death pathways. miRNAs could either promote (in red) or inhibit (in green) cell death by regulating key mediators of intrinsic apoptosis, extrinsic apoptosis and necroptosis

Figure 3

LncRNAs that regulate cell death pathways. LncRNAs could either promote (red) or inhibit (green) cell death by regulating key mediators of intrinsic apoptosis and extrinsic apoptosis

Figure 4

Four patterns of interactions between death-regulating miRNAs and LncRNAs. (a) An miRNA (miR-125b) inhibits an lncRNA (Lnc 7SL) from regulating cell death. (b) An lncRNA (Lnc FER1L4) works as a ceRNA to sponge up and sequester a miRNA (miR-106a-5p) from contacting and degrading death-related target mRNA (PTEN mRNA). (c) A given pair of death-regulating miRNA (miR-145) and lncRNA (Lnc PCGEM1) could suppress each other's expression and/or function. (d) A mutually suppressive pair of death-regulating miRNA (miR-211) and lncRNA (Lnc loc285194) could be subject to certain protein factor (P53)'s regulation