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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE185828 | 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

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

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 [tRNA seq]

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

| PRJNA770961 | ENA

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

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

| PRJNA770962 | 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]

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Selective small molecule PARG inhibitor causes replication fork stalling and cancer cell death.

Project description:Poly(ADP-ribose)ylation (PARylation) by PAR polymerase 1 (PARP1) and PARylation removal by poly(ADP-ribose) glycohydrolase (PARG) critically regulate DNA damage responses; yet, conflicting reports obscure PARG biology and its impact on cancer cell resistance to PARP1 inhibitors. Here, we found that PARG expression is upregulated in many cancers. We employed chemical library screening to identify and optimize methylxanthine derivatives as selective bioavailable PARG inhibitors. Multiple crystal structures reveal how substituent positions on the methylxanthine core dictate binding modes and inducible-complementarity with a PARG-specific tyrosine clasp and arginine switch, supporting inhibitor specificity and a competitive inhibition mechanism. Cell-based assays show selective PARG inhibition and PARP1 hyperPARylation. Moreover, our PARG inhibitor sensitizes cells to radiation-induced DNA damage, suppresses replication fork progression and impedes cancer cell survival. In PARP inhibitor-resistant A172 glioblastoma cells, our PARG inhibitor shows comparable killing to Nedaplatin, providing further proof-of-concept that selectively inhibiting PARG can impair cancer cell survival.

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

Project description: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.

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