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

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

PROVIDER: PRJNA770962 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR16312993.fastq.gz	Fastqsanger.gz
	SRR16312994.fastq.gz	Fastqsanger.gz
	SRR16312995.fastq.gz	Fastqsanger.gz
	SRR16312996.fastq.gz	Fastqsanger.gz

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Similar Datasets

Velcrin-induced selective cleavage of tRNALeu(TAA) by SLFN12 causes cancer cell death [Ribo-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 | GSE185826 | GEO

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

2022-09-01 | GSE185822 | GEO

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

2022-09-01 | GSE185827 | GEO

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

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

| PRJNA770951 | ENA

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

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

| PRJNA770957 | ENA

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

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

| PRJNA770961 | ENA

Anti-Leukemic Effects of Velcrin in SLFN12-Expressing Acute Myeloid Leukemia

Project description:Schlafen 12 (SLFN12) is a member of the Schlafen (SLFN) family of proteins, a group of interferon-stimulated genes with diverse roles in cellular regulation with implications for human malignancies. Accumulating evidence indicates that SLFN family proteins may serve as prognostic markers across various cancer types. In acute myeloid leukemia (AML), SLFN12 is notably overexpressed, which prompted us to investigate its potential as a therapeutic target. Employing a panel of leukemia cell lines, we explored the effects of velcrins, a class of small molecules able to modulate SLFN12 biological activity. Mechanistic studies showed that velcrin treatment increases expression of SLFN12 and promotes SLFN12 complex formation with PDE3A or PDE3B. Functionally, these effects were associated with growth inhibition and induction of apoptosis. Further, velcrin treatment induced potent suppressive effects on the clonogenic capability of primary human AML progenitors and suppressed tumor growth and significantly extended survival in a mouse AML xenograft model. Taken together, these findings highlight the potential of using velcrins as a promising therapeutic strategy for the treatment of AML patients.

2025-09-04 | GSE296195 | GEO

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

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

Anti-Leukemic Effects of Velcrin in SLFN12-Expressing Acute Myeloid Leukemia

Project description:Anti-Leukemic Effects of Velcrin in SLFN12-Expressing Acute Myeloid Leukemia

| PRJNA1258184 | ENA