The dTAG system for immediate and target-specific protein degradation
Open accessAbstract
Dissection of complex biological systems requires target-specific control of the function or abundance of proteins. Genetic perturbations are limited by off-target effects, multicomponent complexity, and irreversibility. Most limiting is the requisite delay between modulation to experimental measurement. To enable the immediate and selective control of single protein abundance, we created a chemical biology system that leverages the potency of cell-permeable heterobifunctional degraders. The dTAG system pairs a novel degrader of FKBP12 F36V with expression of FKBP12 F36V in-frame with a protein of interest. By transgene expression or CRISPR-mediated locus-specific knock-in, we exemplify a generalizable strategy to study the immediate consequence of protein loss. Using dTAG, we observe an unexpected superior antiproliferative effect of pan-BET bromodomain degradation over selective BRD4 degradation, characterize immediate effects of KRAS G12V loss on proteomic signaling, and demonstrate rapid degradation in vivo. This technology platform will confer kinetic resolution to biological investigation and provide target validation in the context of drug discovery.
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The dTAG system (Nabet et al., 2018) was adapted to induce FKBP12F36V-METTL3 acute degradation.
“The dTAG system (Nabet et al., 2018) was adapted to induce FKBP12F36V-METTL3 acute degradation.”
From METTL3 uncouples chromatin accessibility from transcription during retinal development (2025) · cites this paper as Nabet et al., 2018
Bensimon et al. showed that multi-transmembrane proteins from the SLC transporter family could be degraded using dTAG technology.
“Bensimon et al.52 challenged this view by showing that multi-transmembrane proteins from the solute carrier (SLC) transporter family could be degraded using the dTAG technology53.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [53]
Nabet et al. developed a heterologous tagging platform, dTAG, that allows validation of unliganded or yet-to-be-liganded proteins as degradation targets and is enabled for both VHL and CRBN.
“Nabet et al.53,95 have developed a heterologous tagging platform, dTAG, that allows validation of unliganded or yet-to-be-liganded proteins as degradation targets and is enabled for both VHL and CRBN.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [53]
With the exception of newer generations of destabilization domains, these chemical-genetic systems are currently difficult to directly translate into clinical cellular immunotherapies because they use non-human proteins, immunosuppressive controller drugs or non-approved small molecules.
“However, with the exception of newer generations of destabilization domains204, these systems are currently difficult to directly translate into clinical cellular immunotherapies because they use non-human proteins, immunosuppressive controller drugs or non-approved small molecules.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [204]
The efficacy of dTAG-13 to degrade overexpressed dTAG-KRAS-G12V was shown in mice.
“The efficacy of dTAG-13 to degrade overexpressed dTAG–KRAS–G12V was shown in mice, thereby establishing the dTAG system as an elegant FKBP12-based proteolytic system [108].”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [108]
Tag-specific PROTACs such as HaloPROTACs and dTAG-13 offer opportunities for inducible degradation of POIs by using tag-specific PROTACs.
“Therefore, moieties that recognize polypeptide tags, such as HALO and dTAG that could be inserted into POIs by CRISPR/Cas9 genome editing, offer opportunities for inducible degradation of POIs by using the tag-specific PROTACs (such as HaloPROTACs and dTAG-13, respectively) [108, 109].”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [108]
dTAG-13 successfully degraded dTAG-BRD4 fusion proteins generated by CRISPR/Cas9 gene editing, and showed selective, rapid degradation of dTAG-BRD4 upon ligand treatment.
“This approach proved successful in degrading dTAG–BRD4 fusion proteins generated by CRISPR/Cas9 gene editing, and showed selective, rapid degradation of dTAG–BRD4 upon ligand treatment [108].”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [108]
dTAG-13 is a heterobifunctional PROTAC that recruits dTAG to CRBN, and thereby degrades dTAG-fused POIs.
“The authors exploited an FKBP12-F36V-directed ligand called AP1867 (Ariad Pharmaceuticals) to generate a heterobifunctional PROTAC dTAG-13 that recruits dTAG to CRBN, and thereby degrades dTAG-fused POIs [108].”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [108]
dTAG-13 degradation rates vary depending on the POI used, possibly owing to limited accessibility of the dTAG ligand in different subcellular compartments.
“However, the authors noted varying rates of POI degradation, depending on the POI used, possibly owing to limited accessibility of the dTAG ligand in different subcellular compartments [108].”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [108]
dTAG-13 consistently degraded dTAG-KRAS-G12V and dTAG-EZH2 proteins overexpressed in mammalian cells.
“The authors extended this analysis and showcased consistent utility in degrading dTAG–KRAS–G12V and dTAG–EZH2 proteins overexpressed in mammalian cells.”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [108]
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- Authors
- Nabet, B., Roberts, J. M., Buckley, D. L., Paulk, J., Dastjerdi, S., Yang, A., Leggett, A. L., Erb, M. A., Lawlor, M. A., Souza, A., Scott, T. G., Vittori, S., Perry, J. A., Qi, J., Winter, G. E., Wong, K.-K., Gray, N. S., & Bradner, J. E.
- Affiliations
- Harvard University (US)
- Dana-Farber Cancer Institute (US)
- Austrian Academy of Sciences (AT)
- NYU Langone Health (US)
- Corresponding author
- Gray, Nathanael S.
- Bradner, James E.
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2018-03-26
- Volume
- 14
- Issue
- 5
- Pages
- 431-441
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC6295913
- OpenAlex
- W2792453707
- Cited by
- 1,118
- References
- 55
- Citations by year
- 2026: 168 · 2025: 217 · 2024: 176 · 2023: 157 · 2022: 134 · 2021: 125 · 2020: 68 · 2019: 54 · 2018: 17 · 2014: 1
- FWCI
- 23.66
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA166480, R01CA140594, P01CA066996)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Keywords
- heterobifunctional degraders, protein degradation, CRISPR knock-in, target validation, BRD4, KRAS G12V, in vivo degradation, drug target validation, chemical biology
- MeSH terms
- Protein Domains, Bromodomain Containing Proteins, Alleles, Animals, Cytoplasm, Homeostasis, Humans, Ligands, Mutation, Nuclear Proteins, Protein Binding, Transcription Factors, Signal Transduction, Proto-Oncogene Proteins p21(ras), Cell Cycle Proteins, Transgenes, Dimerization, Tacrolimus Binding Protein 1A, Proteomics, NIH 3T3 Cells, Cell Proliferation, Mice, Gene Knock-In Techniques, HEK293 Cells, Proteolysis, CRISPR-Cas Systems
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