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Alt-RPL36 downregulates the PI3K-AKT-mTOR signaling pathway by interacting with TMEM24

ABSTRACT: We characterize non-annotated protein alt-RPL36 which is encoded by RPL36 transcript isoform 2 and overlaps with the RPL36 open reading frame. Its function is examined by specific CRISPR deletion of the GTG start codon located 5' to the RPL36 ATG initiation site. Overall changes in transcript expression are evaluated by comparison with wild type HEK293T cells. RPL36 protein expression is not affected by the altRPL36 start codon deletion.

ORGANISM(S): Homo sapiens

PROVIDER: GSE144979 | GEO | 2020/12/06

REPOSITORIES: GEO

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Alt-RPL36 downregulates the PI3K-AKT-mTOR signaling pathway by interacting with TMEM24

Project description:While thousands of previously unannotated small and alternative open reading frames (alt-ORFs) have recently been revealed in the human genome, the functions of only a handful are currently known, leaving open the question of their biological significance as a class. Using a proteomic strategy for discovery of unannotated short open reading frames in human cells, we report the detection of alt-RPL36, a 148-amino acid protein co-encoded with and overlapping human RPL36. Alt-RPL36 interacts with TMEM24, which transports the phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] precursor phosphatidylinositol from the endoplasmic reticulum to the plasma membrane. Knock-out of alt-RPL36 in HEK 293T cells increased PI(4,5)P2 levels in the plasma membrane and upregulated the PI3K-AKT-mTOR signaling pathway. Remarkably, we find that four serine residues of alt-RPL36 are phosphorylated, and mutation of these four serines to alanine abolished the interaction with TMEM24 and regulation of PI3K signaling. These results implicate alt-RPL36 as a novel regulator of PI(4,5)P2 synthesis upstream of the PI3K-AKT-mTOR signaling pathway, and the first example of a phosphorylated alt-ORF product. More broadly, both alt-RPL36 and RPL36 regulate protein synthesis and cell growth via different molecular mechanisms – AKT signaling and ribosome composition, respectively. One human transcript can therefore express two sequence-independent polypeptides from overlapping ORFs that regulate the same processes via distinct mechanisms.

2020-12-07 | PXD018268 | Pride

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Analysis of gene expression with the Hmga2 allelic series.

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Project description:Most sarcomas have complex karyotype and are characterized by multiple chromosomal rearrangements. Moreover, sarcomas very frequently maintain their telomeres by recombination in the process called Alternative Lengthening of Telomeres (ALT) which enables their continuous growth and immortalization. Previously our group showed that orphan receptors bind specifically to the ALT telomeres and that their presence is important for the ALT mechanism. In these studies we focus on the function of orphan receptors at the telomeres and their contribution to telomeric recombination. We demonstrate that orphan receptors induce proximity of their binding sites in telomeric and genomic context and reveal novel aspects of ALT which are telomere-genome rearrangements which can underlie complexity of sarcomas. Our data perturb the dogma of telomere function in protecting the genome integrity. Here we show that in some cases telomeres may in fact drive genomic instability and chromosomal rearrangements by recombination with genomic sites. Characterization of TRF2 and orphan receptor NR2F/C2 binding sites in ALT (-) and ALT (+) cells.

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Project description:DAXX Suppression of ALT

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Comparative analysis of RNA-seq data from human ALT+ cell lines treated with NR2F2 siRNA

Project description:The Alternative Lengthening of Telomeres (ALT) facilitates telomere lengthening by a DNA strand invasion and copying mechanism. The nuclear receptor NR2F2 can bind to (TCAGGG)n variant repeats within telomeres and it has been proposed that this facilitates telomere interactions in ALT+ cells. However, the role NR2F2 in regulation the gene expression in ALT+ cell lines is unclear. Here, using Next Generation Sequencing (NGS), we characterised the changes in expression profile of three ALT+ cell lines (W-V, WI38VA13/2RA, U2OS) upon transient siRNA mediated downregulation of NR2F2 compared to cells treated with a control siRNA . Among 86 ALT-associated genes, only MND1 showed consistent down-regulation across the three NR2F2-depleted ALT+ cell lines. Altogether our data indicate that NR2F2 it does not play a direct role in the ALT mechanism.

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