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Velcrin-induced selective cleavage of tRNALeu(TAA) by SLFN12 causes cancer cell death [RNA-Seq]

ABSTRACT: Velcrin compounds kill cancer cells expressing high levels of phosphodiesterase 3A (PDE3A) and Schlafen family member 12 (SLFN12) by inducing complex formation between these two proteins, but the mechanism of cancer cell killing by the PDE3A–SLFN12 complex is not fully understood. Here, we report that the physiological substrate of SLFN12 RNase is tRNALeu(TAA). SLFN12 selectively digests tRNALeu(TAA), and velcrin treatment promotes the cleavage of tRNALeu(TAA) by inducing PDE3A–SLFN12 complex formation in vitro. We found that distinct sequences in the variable loop and acceptor stem of tRNALeu(TAA) are required for substrate digestion. Velcrin treatment of sensitive cells results in downregulation of tRNALeu(TAA), ribosome pausing at Leu-TTA codons and global inhibition of protein synthesis. Velcrin-induced cleavage of tRNALeu(TAA) by SLFN12 and the concomitant global inhibition of protein synthesis thus define a new mechanism of apoptosis initiation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE185822 | GEO | 2022/09/01

REPOSITORIES: GEO

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Velcrin-induced selective cleavage of tRNALeu(TAA) by SLFN12 causes cancer cell death [tRNA seq]

Project description:Velcrin compounds kill cancer cells expressing high levels of phosphodiesterase 3A (PDE3A) and Schlafen family member 12 (SLFN12) by inducing complex formation between these two proteins, but the mechanism of cancer cell killing by the PDE3A–SLFN12 complex is not fully understood. Here, we report that the physiological substrate of SLFN12 RNase is tRNALeu(TAA). SLFN12 selectively digests tRNALeu(TAA), and velcrin treatment promotes the cleavage of tRNALeu(TAA) by inducing PDE3A–SLFN12 complex formation in vitro. We found that distinct sequences in the variable loop and acceptor stem of tRNALeu(TAA) are required for substrate digestion. Velcrin treatment of sensitive cells results in downregulation of tRNALeu(TAA), ribosome pausing at Leu-TTA codons and global inhibition of protein synthesis. Velcrin-induced cleavage of tRNALeu(TAA) by SLFN12 and the concomitant global inhibition of protein synthesis thus define a new mechanism of apoptosis initiation.

2022-09-01 | GSE185827 | GEO

Velcrin-induced selective cleavage of tRNALeu(TAA) by SLFN12 causes cancer cell death [Ribo-Seq]

2022-09-01 | GSE185826 | GEO

Structure of PDE3A-SLFN12 complex reveals requirements for activation of SLFN12 RNase

Project description:Garvie CW, Wu X, Papanastasiou M, Lee S, Fuller J, Schnitzler GR, Horner SW, Baker A, Zhang T, Mullahoo JP, Westlake L, Hoyt SH, Toetzl M, Ranaghan M, de Waal L, McGaunn J, Kaplan B, Piccioni F, Yang X, Lange M, Tersteegen A, Raymond D, Lewis TA, Carr SA, Cherniack AD, Lemke C, Meyerson M, Greulich H. 2021. DNMDP and related compounds, or "velcrins", induce complex formation between the phosphodiesterase PDE3A and the SLFN12 protein, leading to a cytotoxic response in cancer cells that express elevated levels of both proteins. The mechanisms by which velcrins induce complex formation, and how the PDE3A-SLFN12 complex causes cancer cell death, are not fully understood. Here, we show that PDE3A and SLFN12 form a heterotetramer stabilized by binding of DNMDP. Interactions between the C-terminal alpha helix of SLFN12 and residues near the active site of PDE3A are required for complex formation, and are further stabilized by interactions between SLFN12 and DNMDP. Moreover, we demonstrate that SLFN12 is an RNase, that PDE3A binding increases SLFN12 RNase activity, and that SLFN12 RNase activity is required for DNMDP response. This new mechanistic understanding will facilitate development of velcrin compounds into new cancer therapies.

2021-06-14 | MSV000087620 | MassIVE

C/D box snoRNA SNORD113-6 guides 2´-O-methylation and directs fragmentation of tRNALeu(TAA) in human arterial fibroblasts

Project description:C/D box small nucleolar RNAs (snoRNAs) transcribed from the DLK1-DIO3 locus are associated with vascular remodelling and cardiovascular disease. None of these snoRNAs has any known targets yet, except for one, AF357425 in mice and SNORD113-6 in humans. We previously showed that this snoRNA targets mRNAs of the integrin signalling pathway and affects arterial fibroblast function. Here, we aimed to identify whether AF357425/SNORD113-6 can also target small RNAs. We overexpressed or inhibited AF357425 in murine fibroblasts and performed small RNA sequencing. Expression of tRNA fragments (tRFs) was predominantly regulated. Compared to overexpression, AF357425 knockdown led to an overall decrease in tRFs, but with an enrichment in smaller tRFs (<30 nucleotides). We focused on tRNA Leucine anti-codon TAA (tRNALeu(TAA)), that has a conserved predicted binding site for AF357425/SNORD113-6. Adjacent to this site, the tRNA is cleaved to form tRFLeu 47-64, in both primary murine fibroblasts and human arterial fibroblasts. We show that AF357425/SNORD113-6 methylates tRNALeu(TAA) and thereby prevents the formation of tRFLeu 47-64. Exposing fibroblasts to oxidative or hypoxic stress, increased AF357425/SNORD113-6 and tRNALeu(TAA) expression, but AF357425/SNORD113-6 knockdown did not lead to an additional formation of tRFLeu 47-64. Thus, independent of cellular stress, AF357425/SNORD113-6 directs site-specific fragmentation of tRNALeu(TAA) via 2’O-ribose-methylation.

2021-12-11 | GSE190537 | GEO

Exogenous SLFN12 reduces in vivo TNBC proliferation and invasion, increases luminal markers and a gene signature that reducts better breast cancer survival in cohort database analysis

Project description:Our results suggest that increased SLFN12 expression modulates TNBC aggressiveness through a gene signature which could offer new targets for treatment.

2023-01-25 | GSE215442 | GEO

C/D box snoRNA SNORD113-6 guides 2´-O-methylation and directs fragmentation of tRNALeu(TAA) in human arterial fibroblasts

Project description:C/D box snoRNA SNORD113-6 guides 2´-O-methylation and directs fragmentation of tRNALeu(TAA) in human arterial fibroblasts

| PRJNA787493 | ENA

Velcrin-induced selective cleavage of tRNALeu(TAA) by SLFN12 causes cancer cell death

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-09-01 | GSE185828 | GEO

Structure of PDE3A-SLFN12 complex reveals requirements for activation of SLFN12 RNase.

Project description: Not available

| S-EPMC8285493 | biostudies-literature

Phosphodiesterase 3A deficient in breast cancer cell

Project description:Analysis of MDA-MB-231 breast tumor cell from knocking-down phosphodiesterase 3A (PDE3A), a cyclic nucleotide phosphodiesterase. Results provide insight into the role of PDE3A in breast tumor progression and metastasis.

2019-09-21 | GSE130569 | GEO

RNA sequencing of intestinal enterocytes pre- and post-Roux-en-Y gastric bypass reveals alteration in gene expression related to enterocyte differentiation, restitution, and obesity

Project description:Background: The intestinal lining renews itself in a programmed fashion that can be affected by adaptation to surgical procedures such as gastric bypass. Results: RNA sequencing suggested significant decreases of gene expression associated with G2/M DNA damage checkpoint regulation of the cell cycle pathway, and significant increases in gene expression associated with CDP-diacylglycerol biosynthesis pathway TCA cycle II pathway, and pyrimidine ribonucleotide salvage pathway after RYGB. Since SLFN12 is reported to influence enterocytic differentiation, we stained mucosa for SLFN12 and observed increased SLFN12 immunoreactivity. We investigated SLFN12 overexpression in HIEC-6 and FHs 74 Int intestinal epithelial cells and observed similar increased expression of the following genes that were also increased after RYGB: HES2, CARD9, SLC19A2, FBXW7, STXBP4, SPARCL1, and UTS. Conclusions: Our data suggests that RYGB promotes SLFN12 protein expression, cellular mechanism and replication pathways, and genes associated with differentiation and restitution (HES2, CARD9, SLC19A2) and obesity-related genes (FBXW7, STXBP4, SPARCL1, UTS).

2022-11-01 | GSE214758 | GEO

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