---
title: "dubTAGs: small molecules for tunable, reversible stabilization of endogenous proteins"
id: "biorxiv-22-dubtags-enable-on-demand-stabilization-for-tunable-and-reversible-control-of"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-22-dubtags-enable-on-demand-stabilization-for-tunable-and-reversible-control-of"
content_type: "clinical_feed_article"
specialty: "Pharmacology"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.09.11.751045v1?rss=1"
published_at: "2026-09-18T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# dubTAGs: small molecules for tunable, reversible stabilization of endogenous proteins
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-22-dubtags-enable-on-demand-stabilization-for-tunable-and-reversible-control-of
- **Specialty:** [Pharmacology](https://medichelpline.com/clinical-feed/pharmacology.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.09.11.751045v1?rss=1)
- **Published At:** 2026-09-18T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- The authors report a new chemical genetic approach, termed **dubTAGs**, consisting of heterobifunctional small molecules that stabilize proteins tagged with **FKBP12F36V** by recruiting endogenous **deubiquitinases**. - dubTAGs are designed as the inverse of dTAG degraders: whereas dTAG recruits E3 ligases to drive proteasomal degradation, dubTAGs recruit deubiquitinases to remove ubiquitin and increase target protein levels on demand. - The system was validated in stem cell–derived cranial neural crest cells (CNCCs) with endogenous transcription factors **SOX9** or **TWIST1** tagged with FKBP12F36V. - The authors identified dubTAG molecules that recruit **OTUB1** or **USP7**, demonstrated ternary complex formation with tagged targets, and showed effective stabilization dependent on deubiquitinase recruitment. - dubTAG-mediated stabilization is reported to be target-specific, tunable, rapid, and capable of reversing prior dTAG-mediated degradation, enabling dynamic control of protein abundance. - The approach was applied to probe how increased endogenous **SOX9** levels alter chromatin accessibility in CNCCs; regulatory elements showed both monotonic and non-monotonic responses tied to distinct sequence features. - dubTAGs are presented as tools to study protein dosage effects in development, disease models, and therapeutic discovery, and to complement existing degradation-based perturbations. - Competing interests disclosed: Jin laboratory has industry funding and J.J. holds equity and consultancy relationships; other authors declared no conflicts. Funding sources listed include NIH grants and private foundations.
## Clinical Analysis & Structured Key Points
dubTAGs enable on-demand stabilization for tunable and reversible control of endogenous protein levels | bioRxiv Skip to main content New Results dubTAGs enable on-demand stabilization for tunable and reversible control of endogenous protein levels View ORCID Profile Sunil Guharajan , View ORCID Profile Xiangyang Song , Qiong Wu , Sachi Sengupta , View ORCID Profile Wenyi Wei , Yan Xiong , Jian Jin , View ORCID Profile Sahin Naqvi doi: https://doi.org/10.64898/2026.09.11.751045 Sunil Guharajan 1 Boston Children's Hospital, Harvard Medical School; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Sunil Guharajan Xiangyang Song 2 Icahn School of Medicine at Mount Sinai; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Xiangyang Song Qiong Wu 2 Icahn School of Medicine at Mount Sinai; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Sachi Sengupta 3 Boston Children's Hospital; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Wenyi Wei 4 Beth Israel Deaconess Medical Center, Harvard Medical School Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Wenyi Wei Yan Xiong 2 Icahn School of Medicine at Mount Sinai; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jian Jin 2 Icahn School of Medicine at Mount Sinai; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Sahin Naqvi 3 Boston Children's Hospital; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Sahin Naqvi For correspondence: sahin.naqvi{at}childrens.harvard.edu Abstract Info/History Metrics Preview PDF Abstract Precise and rapid control over cellular protein levels is essential to dissect complex biological systems. Chemical genetic approaches such as dTAG, in which a target is fused to a degron tag (FKBP12F36V) and degraded upon small molecule-mediated recruitment of E3 ligases, have enabled rapid and tunable control over protein abundance. However, no analogous tool exists to precisely increase protein levels and actively reverse dTAG-mediated degradation. Here, we developed heterobifunctional small molecules (dubTAGs) that stabilize FKBP12F36V-tagged proteins by recruiting endogenous deubiquitinases. Utilizing stem cell-derived cranial neural crest cells (CNCCs) in which the transcription factors SOX9 or TWIST1 are endogenously tagged with FKBP12F36V, we identified OTUB1- or USP7-recruiting heterobifunctional molecules that demonstrated effective target stabilization and ternary complex formation. We demonstrate that dubTAG-mediated protein stabilization is dependent on deubiquitinase recruitment, target-specific, and can tunably and rapidly reverse dTAG-mediated degradation. We applied dubTAGs to assess how stabilizing endogenous SOX9 impacts chromatin accessibility in CNCCs, finding both monotonic and non-monotonic regulatory element responses that are driven by distinct sequence features. dubTAGs are readily applicable tools for investigating the effects of elevated protein levels and tunably reversing targeted degradation, enabling new approaches to study protein dosage effects in development, disease, and therapeutic discovery. Competing Interest Statement The Jin laboratory received research funds from Celgene Corporation, Levo Therapeutics, Inc., Cullgen, Inc. and Cullinan Therapeutics, Inc. J.J. is an equity shareholder in Cullgen, Inc. and a consultant for Cullgen, Inc. J.J. was a cofounder of Cullgen, Inc., a scientific cofounder and scientific advisory board member of Onsero Therapeutics, Inc., and a consultant for EpiCypher, Inc. and Accent Therapeutics, Inc. Other authors declare no conflicts of interest. Funder Information Declared National Institutes of Health , R35GM165577 , 1S10OD025132 , 1S10OD028504 , R00DE032729 Charles H. Hood Foundation, https://ror.org/0550wc655 Richard and Susan Smith Family Foundation, https://ror.org/05j95n956 Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license . Back to top Previous Next Posted September 18, 2026. Download PDF Email Thank you for your interest in spreading the word about bioRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. 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Share dubTAGs enable on-demand stabilization for tunable and reversible control of endogenous protein levels Sunil Guharajan , Xiangyang Song , Qiong Wu , Sachi Sengupta , Wenyi Wei , Yan Xiong , Jian Jin , Sahin Naqvi bioRxiv 2026.09.11.751045; doi: https://doi.org/10.64898/2026.09.11.751045 Share This Article: Copy Citation Tools dubTAGs enable on-demand stabilization for tunable and reversible control of endogenous protein levels Sunil Guharajan , Xiangyang Song , Qiong Wu , Sachi Sengupta , Wenyi Wei , Yan Xiong , Jian Jin , Sahin Naqvi bioRxiv 2026.09.11.751045; doi: https://doi.org/10.64898/2026.09.11.751045 Citation Manager Formats BibTeX Bookends EasyBib EndNote (tagged) EndNote 8 (xml) Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Tweet Widget Facebook Like Google Plus One Subject Areas All Articles Animal Behavior and Cognition (8009) Biochemistry (18728) Bioengineering (14866) Bioinformatics (44390) Biophysics (22582) Cancer Biology (19708) Cell Biology (26891) Clinical Trials (138) Developmental Biology (13960) Ecology (20996) Epidemiology (2067) Evolutionary Biology (25436) Genetics (16161) Genomics (23495) Immunology (18691) Microbiology (42448) Molecular Biology (18050) Neuroscience (93403) Paleontology (700) Pathology (2977) Pharmacology and Toxicology (5088) Physiology (8109) Plant Biology (15994) Scientific Communication and Education (2095) Synthetic Biology (4558) Systems Biology (10231) Zoology (2388)
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