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  • 1
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    Taurine linked with healthy aging
    American Association for the Advancement of Science (AAAS) ; 2023
    In:  Science Vol. 380, No. 6649 ( 2023-06-09), p. 1010-1011
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 380, No. 6649 ( 2023-06-09), p. 1010-1011
    Abstract: Taurine is an amino acid, but it contains a sulfonic acid and a b-amine that make it structurally and chemically distinct from the more familiar amino acids that form proteins. Although nearly absent in most plants, taurine makes up as much as 0.1% of the body weight of animals ( 1 ). Humans synthesize taurine but depend on exogenous sources in early life when production is insufficient to support development, making it semi-essential. In species with very low synthesis, such as cats, taurine remains essential throughout adulthood; inadequate intake leads rapidly to retinal damage, immunological issues, and cardiomyopathy ( 2 ). In humans, small clinical trials of taurine supplementation in adults have suggested benefits in metabolic and inflammatory diseases ( 3 , ( 4 ). Yet, precisely what taurine does in most cases remains poorly understood. On page 1028 of this issue, Singh et al . ( 5 ) provide evidence that taurine maintains health in aged animal models.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.adi3025
    RVK:
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    RVK:
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2023
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  • 2
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    Velcrin-induced selective cleavage of tRNALeu(TAA) by SLFN12 causes cancer cell death
    Springer Science and Business Media LLC ; 2023
    In:  Nature Chemical Biology Vol. 19, No. 3 ( 2023-03), p. 301-310
    Details
    In: Nature Chemical Biology, Springer Science and Business Media LLC, Vol. 19, No. 3 ( 2023-03), p. 301-310
    Type of Medium: Online Resource
    ISSN: 1552-4450 , 1552-4469
    URL: Article
    DOI: 10.1038/s41589-022-01170-9
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
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  • 3
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    Abstract 879: SLFN12-mediated depletion of tRNA-Leu-TAA by velcrin treatment induces ribosome pausing at Leu-TTA codons and represses global translation initiation
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 879-879
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 879-879
    Abstract: Velcrin compounds kill cancer cells expressing high levels of PDE3A and 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. We previously determined that SLFN12 is an RNase, that PDE3A binding upregulates SLFN12 RNase activity, and that SLFN12 RNase activity is required for velcrin response. Here, we report that the depletion of tRNA-Leu-TAA by velcrin treatment induces ribosome pausing at Leu-TTA codons and global inhibition of protein synthesis. We performed ribosome profiling in HeLa cells treated with DMSO or DNMDP and found that ribosome footprints containing Leu-TTA codons at the A-site of the ribosome were significantly more abundant in DNMDP-treated cells than in cells treated with DMSO, indicating a pausing or stalling of ribosomes at Leu-TTA upon velcrin treatment. Although the overall number of ribosome pausing sites across the transcriptome was doubled by DNMDP treatment, ribosome pausing at Leu-TTA was increased & gt 1000-fold, also resulting in an increased number of genes with TTA pause sites. Even though Leu-TTA is a rare codon, over 70% of all transcripts contain at least one TTA codon, implying that ribosome pausing at TTA codons could directly impact many genes. Genes with TTA pause sites most enriched upon velcrin treatment prominently include those involved in control of mRNA translation and protein homeostasis. These results imply that, in addition to direct effects on mRNA translation due to ribosome pausing, indirect effects could occur due to decreased availability of particular components of the translation machinery, resulting in a widespread impact on protein synthesis. To test our hypothesis, we measured the effects of velcrin treatment on nascent protein abundance. Treatment of HeLa cells with DNMDP resulted in downregulation of newly synthesized proteins, whereas no significant changes in total protein content were observed. Downregulation of protein translation was observed only in velcrin-sensitive cell lines, indicating that inhibition of protein translation could be the mechanism of action of cancer cell killing by PDE3A-SLFN12 complex formation. Citation Format: Stephanie Hoyt, Sooncheol Lee, Joseph McGaunn, Andrew Cherniack, Matthew Meyerson, Heidi Greulich. SLFN12-mediated depletion of tRNA-Leu-TAA by velcrin treatment induces ribosome pausing at Leu-TTA codons and represses global translation initiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 879.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-879
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 4
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    Structure of PDE3A-SLFN12 complex reveals requirements for activation of SLFN12 RNase
    Springer Science and Business Media LLC ; 2021
    In:  Nature Communications Vol. 12, No. 1 ( 2021-07-16)
    Details
    In: Nature Communications, Springer Science and Business Media LLC, Vol. 12, No. 1 ( 2021-07-16)
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 2041-1723
    URL: Article
    DOI: 10.1038/s41467-021-24495-w
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
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  • 5
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    Abstract 1219: Deep mutational scanning of PDE3A identifies residues required for DNMDP response
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1219-1219
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1219-1219
    Abstract: PDE3A-SLFN12 complex formation is induced by a class of compounds, now called “velcrins”, exemplified by the small molecule, DNMDP. Cancer cells that express elevated levels of PDE3A and SLFN12 are sensitive to a velcrin-mediated cytotoxic response, which is independent of PDE3A inhibition. However, the details of complex formation have not yet been revealed. We solved the crystal structure of PDE3A with a series of ligands bound to the active site and found that PDE3A exists as a dimer, and velcrin binding does not cause any obvious structural changes in the PDE3A protein structure. Hydrogen-deuterium exchange (HDX-MS) experiments with velcrin-bound PDE3A in the absence and presence of SLFN12 identified three regions of PDE3A that are shielded from solvent as a result of velcrin-induced SLFN12 binding. Two of these regions are near the velcrin binding site, and the third region lies at the PDE3A homodimerization interface. In order to further investigate the structural relationship between PDE3A, DNMDP, and SLFN12, we took a deep-mutation scanning (DMS) approach to identify residues of PDE3A that impact DNMDP sensitivity. A library of PDE3A alleles was developed in which the sequence encoding amino acids 668-1141, including the PDE3A catalytic domain, was substituted with a codon for every other possible amino acid or a stop codon in the context of the full-length cDNA. The library was transduced into PDE3A-knockout GB1 glioblastoma cells and assessed for survival in the presence of DMSO or DNMDP. Corroborating the HDX-MS data, we identified three regions of PDE3A in which missense mutations abrogated DNMDP response: the active site, the homodimerization surface, and an alpha helix containing amino acid F914. We confirmed that mutations of F914 and the homodimer interface retain the ability to bind resin-conjugated compound but fail to complex with SLFN12. Taken together, the HDX and DMS results suggest that PDE3A dimerization is required to stabilize velcrin-induced SLFN12 binding and implicate the alpha helix containing F914 as the SLFN12 binding interface of PDE3A. Citation Format: Xiaoyun Wu, Malvina Papanastasiou, Gavin Schnitzler, Colin Garvie, Stephanie Hoyt, Terry Zhang, James Mullahoo, Andrew Baker, Joseph McGaunn, Bethany Kaplan, Sooncheol Lee, Martin Lange, Steven Carr, Xiaoping Yang, Federica Piccioni, Andrew Cherniack, Matthew Meyerson, Heidi Greulich. Deep mutational scanning of PDE3A identifies residues required for DNMDP response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1219.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-1219
    RVK:
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    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 6
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    Abstract A159: Mechanisms of uveal melanoma sensitivity to velcrin treatment and SLFN12-mediated cancer cell death
    American Association for Cancer Research (AACR) ; 2023
    In:  Molecular Cancer Therapeutics Vol. 22, No. 12_Supplement ( 2023-12-01), p. A159-A159
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 22, No. 12_Supplement ( 2023-12-01), p. A159-A159
    Abstract: Velcrins are a novel class of compounds that kill cancer cells expressing elevated levels of PDE3A and SLFN12. These compounds induce PDE3A-SLFN12 heterotetramer complex formation, resulting in upregulation of the RNase activity of SLFN12. SLFN12 cleaves tRNA-Leu-TAA, which leads to the inhibition of global translation and, consequently, apoptosis of cells expressing sufficient levels of both proteins. Uveal melanoma, a type of melanoma that occurs in the eye, is genomically distinct from cutaneous melanoma. Whereas mutations of BRAF, NRAS, KRAS, and HRAS are common in cutaneous melanoma, uveal melanomas instead harbor mutually exclusive mutations of the G protein alpha subunits, GNAQ and GNA11. Around 50% of patients will develop metastatic disease with a very poor prognosis. Immunotherapy is not effective for these patients, nor are any targeted therapies available beyond tebentafusp, with an ORR of 9%.  We found that a subset of uveal melanoma cell lines expresses elevated levels of PDE3A and SLFN12 and is sensitive to velcrin treatment.  We are currently assessing whether velcrin treatment of these cell lines results in cleavage of tRNA-Leu-TAA, inhibition of protein synthesis, and tumor cell death, with the goal of developing a new treatment for uveal melanoma patients.   To further understand the mechanism of velcrin-induced cancer cell death, we hypothesized that the primary function of PDE3A in the PDE3A-SLFN12 heterotetramer is the dimerization of SLFN12. Based on our cryo-EM structure of the PDE3A-SLFN12 complex, we identified SLFN12 I131 as a critical residue in the SLFN12 homodimer interface. We showed that a SLFN12 I131Q mutation disrupts SLFN12 dimerization and prevents tRNA-Leu-TAA cleavage in vitro. We have also shown that wild-type SLFN12 can dimerize independently of PDE3A or PDE3A-velcrin interactions. In PDE3A-depleted cells, the overexpression of wild-type SLFN12 results in cell death. We are currently testing SLFN12 I131Q for its ability to initiate SLFN12-dependent cytotoxicity in cells. Additionally, we are preparing different SLFN12 constructs that would allow us to induce chemical dimerization of SLFN12 and we plan to test if the forced dimerization of SLFN12 rescues its RNase activity and results in cell death. Citation Format: Kristyna Kotynkova, Sawyer Andersen, Colin Garvie, Xiaoyun Wu, Sooncheol Lee, Joseph McGaunn, Bethany Kaplan, Moony Tseng, Andrew D Cherniack, Matthew Meyerson, Heidi Greulich. Mechanisms of uveal melanoma sensitivity to velcrin treatment and SLFN12-mediated cancer cell death [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A159.
    Type of Medium: Online Resource
    ISSN: 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-23-A159
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 7
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    Unbiased approach for the identification of molecular mechanisms sensitive to chemical exposures
    Elsevier BV ; 2021
    In:  Chemosphere Vol. 262 ( 2021-01), p. 128362-
    Details
    In: Chemosphere, Elsevier BV, Vol. 262 ( 2021-01), p. 128362-
    Type of Medium: Online Resource
    ISSN: 0045-6535
    URL: Article
    DOI: 10.1016/j.chemosphere.2020.128362
    RVK:
    AR 10100
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2021
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  • 8
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    Abstract 867: Velcrin-induced cleavage of tRNA-Leu-TAA by SLFN12 RNase causes cancer cell death
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 867-867
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 867-867
    Abstract: Velcrins are small molecules that induce apoptosis of cancer cells expressing high levels of phosphodiesterase 3A (PDE3A) and schlafen family member 12 (SLFN12) by inducing PDE3A-SLFN12 complex formation. Recently, we found that SLFN12 is an RNase and PDE3A binding dramatically activates SLFN12 RNase activity, resulting in velcrin-mediated apoptosis. However, the mechanism of cancer cell death by the PDE3A-SLFN12 complex is poorly understood. In this study, we found that SLFN12 specifically recognizes tRNA-Leu-TAA and induces its cleavage in velcrin-sensitive cell lines. According to tRNA-sequencing, tRNA-Leu-TAA isodecoders decreases by 2-fold to 5-fold in Hela cells treated with DNMDP compared to DMSO control, while other tRNAs are not differentially expressed. Down-regulation of tRNA-Leu-TAA by velcrin treatment is observed only in velcrin-sensitive cell lines but not insensitive cell lines. Furthermore, we tested whether SLFN12 digests tRNA-Leu-TAA in vitro. Purified wild-type SLFN12 cleaves tRNA-Leu-TAA but not heat-denatured or catalytically inactive SLFN12. Even though tRNA-Leu-TAA is weakly digested by low concentrations of SLFN12, co-incubation with purified PDE3A increases SLFN12 RNase activity, which is even further upregulated by velcrin treatment. To verify specificity for tRNA-Leu-TAA, we assessed activity of SLFN12 against a panel of in vitro transcribed tRNAs. We found that purified SLFN12 is significantly more efficient at degrading tRNA-Leu-TAA when compared with tRNA-Leu-TAG or tRNAs for other amino acids. Digestion of tRNA-leu-TAA by SLFN12 could inhibit mRNA translation due to the delivery of leucine amino acid to elongating ribosomes. To test this hypothesis, we designed the mutant tRNA-Leu-[CAG:TAA] in which the anticodon of tRNA-Leu-CAG was replaced by TAA anticodon. Ectopic expression of wild-type tRNA-Leu-TAA or tRNA-Leu-CAG has no effect on viability of DNMDP-treated cells, whereas expression of tRNA-Leu-[CAG:TAA] genes partially rescues the cells from DNMDP-induced cytotoxicity. These data confirm that impaired leucine delivery is responsible at least in part for the observed effects of DNMDP treatment. Citation Format: Sooncheol Lee, Stephanie Hoyt, Xiaoyun Wu, Colin Garvie, Joseph McGaunn, Andrew D. Cherniack, Matthew Meyerson, Heidi Greulich. Velcrin-induced cleavage of tRNA-Leu-TAA by SLFN12 RNase causes cancer cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 867.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-867
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 9
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    Abstract ND04: BAY 2666605: The first PDE3A-SLFN12 complex inducer for cancer therapy
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. ND04-ND04
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. ND04-ND04
    Abstract: Velcrin compounds are a class of small molecules that induce complex formation between PDE3A and SLFN12, killing cancer cells that express elevated levels of these two proteins by a mechanism independent of PDE3A enzymatic inhibition. Instead, PDE3A binding stimulates the RNase activity of SLFN12, resulting in cleavage of the specific SLFN12 substrate, tRNA-Leu-TAA. Cleavage of tRNA-Leu-TAA in turn causes ribosomal pausing, inhibition of protein synthesis, and cancer cell death. Unlike traditional targeted therapies that leverage dependencies created in cancer cells by genomic alterations, velcrins instead kill cancer cells by a gain-of-function mechanism dependent on the RNase activity of SLFN12. In a collaboration between the Broad Institute and Bayer Pharmaceuticals, we developed the first velcrin, BAY 2666605, to enter Phase I clinical trials. BAY 2666605 is active in cell line and patient-derived xenografts of several tumor types, specifically where elevated levels of the two biomarkers, PDE3A and SLFN12, are expressed. Biomarker-positive tumors are especially enriched among melanomas, and we have consistently observed tumor regression in biomarker-positive melanoma tumor models in vivo. BAY 2666605 furthermore shows drug-like properties, excellent brain penetration, increased stimulation of SLFN12 RNase activity, and reduced inhibition of PDE3A enzymatic activity compared with most other velcrins and approved PDE3A inhibitors. BAY 2666605 has recently entered a First-in-Human study (NCT04809805) in patients with advanced solid tumors that co-express PDE3A and SLFN12, including melanoma, ovarian cancer, and sarcoma. Citation Format: Stefan Gradl, Sooncheol Lee, Martin Lange, Xiaoyun Wu, Silvia Goldoni, Timothy Lewis, Charlotte Kopitz, Colin Garvie, Philip Lienau, Stephanie Hoyt, Henrik Seidel, Stephan Kaulfuss, Manuel Ellermann, Luc de Waal, Adrian Tersteegen, Sven Golfier, Detlev Suelzle, Christa Hegele-Hartung, James Carr, Frederick Brookfield, Michael Bruening, Melanie Berthold, Thibaud Jourdan, Monica Schenone, Galen Gao, Joseph McGaunn, Antje Wengner, Elisa Aquilanti, Franziska Siegel, Marine Garrido, Annette Walter, Isabelle Genvresse, Andrew Cherniack, Stuart Schreiber, Knut Eis, Ashley Eheim, Matthew Meyerson, Heidi Greulich. BAY 2666605: The first PDE3A-SLFN12 complex inducer for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr ND04.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-ND04
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 10
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    Abstract 54: Cryo-EM structure of the PDE3A-SLFN12 complex reveals requirements for the activation of SLFN12 RNase and DNMDP-induced cancer cell killing
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 54-54
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 54-54
    Abstract: We have identified a novel mechanism of selective cancer cell-killing, whereby small molecules such as DNMDP induce complex formation between phosphodiesterase 3A (PDE3A) and a poorly characterized protein, SLFN12, that leads to downstream cell death (de Waal et al., Nat Chem Biol 2016; Lewis et al., ACS Med Chem Letters, 2019; Wu et al., J Bio Chem 2020). This process therefore relies on the presence and interaction of these two proteins, rather than a pre-existing dependency, as is the mechanism of many currently available cancer therapies. While complex formation is required for cancer cell killing, the molecular basis for complex induction and the activity of the complex that leads to cell death have not been described. In this study, we employed cryogenic electron microscopy (cryo-EM) to deduce the high-resolution structure of the DNMDP-induced PDE3A-SLFN12 complex. The solved structure includes DNMDP-bound PDE3A at 2.97 Å, as well as the structure of the full length SLFN12 at 2.76 Å. We found that the entire complex consists of a 2:2 hetero-tetramer with the C-terminal alpha-helix of SLFN12 reaching into the DNMDP-occupied substrate binding pocket of PDE3A and contacting both DNMDP and active site residues of PDE3A. The binding of DNMDP to PDE3A does not induce structural changes, but rather creates an adhesive surface at the entrance of the substrate binding pocket, which allows for stable binding of SLFN12. We have named DNMDP and similar PDE3A-SLFN12 complex inducing compounds “velcrins”, after the adhesive fabric. Site-directed mutagenesis confirmed that residues on the SLFN12 C-terminal helix are required for DNMDP-induced cell death. Based on homology to the SLFN13, we predicted that SLFN12 would also encode an RNase. Indeed, purified SLFN12 protein cleaved ribosomal RNA in vitro and mutation of the putative catalytic residues abolished this activity. Importantly, catalytically dead SLFN12 mutants failed to mediate DNMDP-induced cell killing while retaining the ability to complex with PDE3A. Consistent with the requirement of SLFN12 RNase activity for DNMDP-induced cell death, overexpression of wild-type SLFN12 alone was cytotoxic, whereas overexpression of catalytically dead SLFN12 was not. The RNase activity of SLFN12 in vitro was stimulated in the presence of DNMDP and PDE3A, suggesting that the mechanism of DNMDP-induced cell killing involves activation of the SLFN12 RNase. Intriguingly, SLFN12 homodimer interface mutants were no longer cytotoxic when overexpressed, but still supported DNMDP-induced cell killing. We hypothesize that PDE3A, an obligate dimer, activates SLFN12 RNase activity by stabilizing the dimeric form of SLFN12. Citation Format: Xiaoyun Wu, Colin Garvie, Sooncheol Lee, Steven Horner, Andrew Baker, Marcus Toetzl, Joseph McGaunn, Bethany Kaplan, Luc de Waal, Martin Lange, Timothy Lewis, Chris Lemke, Matthew Meyerson, Heidi Greulich. Cryo-EM structure of the PDE3A-SLFN12 complex reveals requirements for the activation of SLFN12 RNase and DNMDP-induced cancer cell killing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 54.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-54
    RVK:
    XA 36000
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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