Long non-coding RNAs and p53 regulation

Abstract

The advent of novel and high-throughput sequencing (next generation) technologies allowed for the sequencing of the genome at an unprecedented depth. The majority of transcribed RNAs have been classified as non-coding RNAs. Among them, long non-coding RNAs (lncRNAs) are emerging as important regulators in many biological processes. Here, we discuss the role of those lncRNAs which are under the control of p53 or that are able to regulate its activity, due to the central role of p53 pathway in many conditions. We also briefly discussed the emerging need of having novel strategies and computational tools to completely unravel the multifaceted roles of lncRNAs and to pave the way to the development of novel diagnostic and therapeutic applications based on these peculiar molecules.

Figure 1

Proposed model for the role of LincRNA-p21 in the p53 transcriptional response. The induction of p53 activates the transcription of LincRNA-p21 by binding to its promoter (upper left). LincRNA-p21 binds to hnRNP-K and acts to repress genes that are downregulated as part of the canonical p53 transcriptional response. (Adapted from [24]).

Figure 2

Model of coding and non-coding transcripts at the CDKN1A locus coordinating the DNA damage response. After DNA damage, p53 binding at the CDKN1A locus coordinately activates transcription of CDKN1A as well as non-coding transcripts PANDA and LincRNA-p21. CDKN1A mediates cell cycle arrest, PANDA blocks apoptosis through NF-YA, and LincRNA-p21 mediates gene silencing through recruitment of hnRPK. (Adapted from [26]).

Figure 3

The potential role of LincRNA-EPS in erythropoiesis. (A) LincRNA-EPS represses Pycard gene to inhibit apoptosis of red blood cells progenitors. LincRNA-EPS may bind the Pycard gene and inhibit its transcription by recruiting transcriptional repressor complexes; (B) Knockdown of LincRNA-EPS allows the transcription of Pycard, which in turn activates intercellular caspases and induces apoptosis. (Adapted from [31]).

Figure 4

In the p53 pathway, MEG3 may activate p53 directly by RNA-protein interaction or indirectly by suppressing MDM2, resulting in selective activation of p53 downstream targets such as GDF-15 with both anti-proliferative and tumor suppressive functions. The association of H19 with p53 determines tumorigenesis regulation. The role of the lncRNAs LincRNA-p21, PANDA and LincRNA-EPS have been discussed in the text.