TP53-inducible putative long noncoding RNAs encode functional polypeptides that suppress cell proliferation

Abstract

Polypeptides encoded by long non-coding RNAs (lncRNAs) are a novel class of functional molecules. However, whether these hidden polypeptides participate in the TP53 pathway and play a significant biological role is still unclear. Here, we discover that TP53-regulated lncRNAs encode peptides, two of which are functional in various human cell lines. Using ribosome profiling and RNA-seq approaches in HepG2 cells, we systematically identified more than 300 novel TP53-regulated lncRNAs and further confirmed that fifteen of these TP53-regulated lncRNAs encode peptides. Furthermore, several peptides were validated by multiple mass spectrometry measures. Ten of the novel translational lncRNAs were directly inducible by TP53 in response to DNA damage. Notably, we showed that the TP53-inducible peptides TP53LC02 and TP53LC04, but not their lncRNAs, could suppress cell proliferation. TP53LC04 peptide also had a function associated with cell proliferation by regulating the cell cycle in response to DNA damage. This study demonstrates that TP53-inducible lncRNAs encode new functional peptides, leading to the enlargement of the components of TP53 tumor suppressor network and providing novel potential targets for cancer therapy.

NAP-seq reveals multiple classes of structured noncoding RNAs with regulatory functions

“…To demonstrate the utility of NAP-seq-NGS for identifying previously uncharacterized napRNAs compared to the GENCODE database (human release 30 and mouse release 23) 25 , in different cells and under different conditions, we further profiled the transcriptomes of 3 different stress responses (poly (I:C), adriamycin (ADR), and CoCl 2 ) in human HepG2 cells and 4 different myoblast differentiation stages in the mouse skeletal muscle cell line C2C12, as well as the abovementioned three cell lines. In these stress responses, poly (I:C) mimics double-stranded RNA to induce the activation of immune response 26 ; ADR causes DNA damage, triggering cells to activate their DNA damage repair machinery 27 , 28 ; CoCl 2 artificially induces hypoxia 29 , which has allowed the characterization of the hypoxia response at the cellular, biochemical and molecular levels 30 . Moreover, we developed a computational tool, napSeeker, to determine the full-length sequences of napRNAs from total NAP-seq data (Supplementary Fig.…”

Decoding the lncRNAome Across Diverse Cellular Stresses Reveals Core p53-effector Pan-cancer Suppressive lncRNAs

“…It was recently reported that following p53 activation, 380 altered lncRNAs were identified in liver HepG2 cells ( 49 ). We determined that compared with background lncRNAs, a significantly ( P = 1.27 × 10 −31 ; hypergeometric test) higher proportion of our predicted p53-effector lncRNAs overlapped with these altered lncRNAs, increasing confidence that our identified lncRNAs are core p53 targets.…”

A Mammalian Conserved Circular RNA CircLARP1B Regulates Hepatocellular Carcinoma Metastasis and Lipid Metabolism

“…The 5′ portion of LARP1B mRNA is heavily bound by ribosomes through analyzing available ribosome profiling sequencing (Ribo‐seq) data from HCC cell lines (GSE125757, GSE128320, and GSE147840) (Figure S5b , Supporting Information). [ 53 , 54 , 55 ] One possibility is that LARP1B mRNA is actively involved in translation, and the HNRNPD sites present in its 5′ are thus not available for HNRNPD binding.…”