The DOI matches its Crossref record; 45 of the 47 references it cites were found in a registry or an index.
BET Bromodomain Proteins Function as Master Transcription Elongation Factors Independent of CDK9 Recruitment
Open accessAbstract
Processive elongation of RNA Polymerase II from a proximal promoter paused state is a rate-limiting event in human gene control. A small number of regulatory factors influence transcription elongation on a global scale. Prior research using small-molecule BET bromodomain inhibitors, such as JQ1, linked BRD4 to context-specific elongation at a limited number of genes associated with massive enhancer regions. Here, the mechanistic characterization of an optimized chemical degrader of BET bromodomain proteins, dBET6, led to the unexpected identification of BET proteins as master regulators of global transcription elongation. In contrast to the selective effect of bromodomain inhibition on transcription, BET degradation prompts a collapse of global elongation that phenocopies CDK9 inhibition. Notably, BRD4 loss does not directly affect CDK9 localization. These studies, performed in translational models of T cell leukemia, establish a mechanism-based rationale for the development of BET bromodomain degradation as cancer therapy.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“we focused on two BET Bromodomain targeting PROTACs: dBET6 (CRBN-based) and ARV-771 (VHL-based) that have matched cellular potency, including in the near-haploid human leukemia cell line KBM7 (Extended Data Fig. 1A)26,27.”
From Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders (2023) · cites this paper as [27]
In the citing paper
“These differences could be attributed to the distinct recruitment ligases used by MZ1 (VHL) or dBET6 (CRBN), as well as the established differences in selectivity for the BBDs, where MZ1 preferentially degrades BRD4 (17), whereas dBET6 degrades BRD2, BRD3 and BRD4, equivalently (16).”
From The drug efflux pump MDR1 promotes intrinsic and acquired resistance to PROTACs in cancer cells (2022) · cites this paper as [16]
In the citing paper
“Later, they optimized the linker and found a more potent PROTAC (dBET6) that showed better efficacy against T-ALL compared with JQ1 [43].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [43]
In the citing paper
“Therefore, profiling the changes in global protein expression by proteomics will be helpful to appreciate the potential off-target toxicities of PROTACs [3, 4, 43].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [43]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
STAR: ultrafast universal RNA-seq aligner
Dobin, A., Davis, C. A., Schlesinger, F., Drenkow, J., Zaleski, C., Jha, S., Batut, P., Chaisson, M., & Gingeras, T. R. (2013) · Bioinformatics · doi:10.1093/bioinformatics/bts635 · Cited by 51,709
Ultrafast and memory-efficient alignment of short DNA sequences to the human genome.
Langmead, B., Trapnell, C., Pop, M., & Salzberg, S. L. (2009) · Genome Biology · doi:10.1186/gb-2009-10-3-r25 · Cited by 21,849
HTSeq—a Python framework to work with high-throughput sequencing data
Anders, S., Pyl, P. T., & Huber, W. (2015) · Bioinformatics · doi:10.1093/bioinformatics/btu638 · Cited by 21,464
Model-based Analysis of ChIP-Seq (MACS)
Zhang, Y., Liu, T., Meyer, C. A., Eeckhoute, J., Johnson, D. S., Bernstein, B. E., Nusbaum, C., Myers, R. M., Brown, M., Li, W., et al. (2008) · Genome Biology · doi:10.1186/gb-2008-9-9-r137 · Cited by 18,386
Trapnell, C., Williams, B. A., Pertea, G., Mortazavi, A., Kwan, G., van Baren, M. J., Salzberg, S. L., Wold, B. J., & Pachter, L. (2010) · Nature Biotechnology · doi:10.1038/nbt.1621 · Cited by 15,556
Genome engineering using the CRISPR-Cas9 system
Ran, F. A., Hsu, P. D., Wright, J., Agarwala, V., Scott, D. A., & Zhang, F. (2013) · Nature Protocols · doi:10.1038/nprot.2013.143 · Cited by 11,133
Master Transcription Factors and Mediator Establish Super-Enhancers at Key Cell Identity Genes
Whyte, W. A., Orlando, D. A., Hnisz, D., Abraham, B. J., Lin, C. Y., Kagey, M. H., Rahl, P. B., Lee, T. I., & Young, R. A. (2013) · Cell · doi:10.1016/j.cell.2013.03.035 · Cited by 4,143
Self-citationSelective Inhibition of Tumor Oncogenes by Disruption of Super-Enhancers
Lovén, J., Hoke, H. A., Lin, C. Y., Lau, A., Orlando, D. A., Vakoc, C. R., Bradner, J. E., Lee, T. I., & Young, R. A. (2013) · Cell · doi:10.1016/j.cell.2013.03.036 · Cited by 2,961
Self-citationMonitoring Drug Target Engagement in Cells and Tissues Using the Cellular Thermal Shift Assay
Molina, D. M., Jafari, R., Ignatushchenko, M., Seki, T., Larsson, E. A., Dan, C., Sreekumar, L., Cao, Y., & Nordlund, P. (2013) · Science · doi:10.1126/science.1233606 · Cited by 2,261
A tissue-specific atlas of mouse protein phosphorylation and expression
Huttlin, E. L., Jedrychowski, M. P., Elias, J. E., Goswami, T., Rad, R., Beausoleil, S. A., Villén, J., Haas, W., Sowa, M. E., & Gygi, S. P. (2010) · Cell · doi:10.1016/j.cell.2010.12.001 · Cited by 1,778
Cited by
Sorted by citations
The dTAG system for immediate and target-specific protein degradation
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., et al. (2018) · Nature Chemical Biology · doi:10.1038/s41589-018-0021-8 · Cited by 1,118
Self-citationModulation of cellular processes by histone and non-histone protein acetylation
Shvedunova, M., & Akhtar, A. (2022) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-021-00441-y · Cited by 1,007
Eukaryotic core promoters and the functional basis of transcription initiation
Haberle, V., & Stark, A. (2018) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-018-0028-8 · Cited by 774
A Potent and Selective Small-Molecule Degrader of STAT3 Achieves Complete Tumor Regression In Vivo
Bai, L., Zhou, H., Xu, R., Zhao, Y., Chinnaswamy, K., McEachern, D., Chen, J., Yang, C.-Y., Liu, Z., Wang, M., et al. (2019) · Cancer Cell · doi:10.1016/j.ccell.2019.10.002 · Cited by 652
Plasticity in binding confers selectivity in ligand-induced protein degradation
Nowak, R. P., DeAngelo, S. L., Buckley, D., He, Z., Donovan, K. A., An, J., Safaee, N., Jedrychowski, M. P., Ponthier, C. M., Ishoey, M., et al. (2018) · Nature Chemical Biology · doi:10.1038/s41589-018-0055-y · Cited by 615
Self-citation
Metadata
- Authors
- Winter, G. E., Mayer, A., Buckley, D. L., Erb, M. A., Roderick, J. E., Vittori, S., Reyes, J. M., di Iulio, J., Souza, A., Ott, C. J., Roberts, J. M., Zeid, R., Scott, T. G., Paulk, J., Lachance, K., Olson, C. M., Dastjerdi, S., Bauer, S., Lin, C. Y., Gray, N. S., Kelliher, M. A., Churchman, L. S., & Bradner, J. E.
- Affiliations
- Austrian Academy of Sciences (AT)
- Harvard University (US)
- Dana-Farber Cancer Institute (US)
- University of Massachusetts Chan Medical School (US)
- Corresponding author
- Churchman, L. Stirling
- Bradner, James E.
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2017-07
- Volume
- 67
- Issue
- 1
- Pages
- 5-18.e19
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC5663500
- OpenAlex
- W2733066269
- Cited by
- 465
- References
- 47
- Citations by year
- 2026: 43 · 2025: 59 · 2024: 44 · 2023: 54 · 2022: 66 · 2021: 59 · 2020: 43 · 2019: 50 · 2018: 42 · 2017: 5
- FWCI
- 15.64
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- Funders
- William Lawrence and Blanche Hughes Foundation
- NIH (R01-HG007173, R01-GM117333, R01-CA176745, P01-CA109901)
- EMBO long-term fellowship (ALTF 39-2013)
- Damon Runyon Cancer Research Foundation (DRG-2196-14)
- Human Frontier Science Program (LT000314/2013-L)
- EMBO (ALTF858-2012)
- Swiss National Science Foundation Postdoc Mobility Fellowship
- American Cancer Society Post-doctoral fellowship (125087-PF-13-247-01-LIB)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- BET proteins, BRD4, transcription elongation, RNA polymerase II, CDK9, bromodomain inhibitors, JQ1, enhancers, T-cell leukemia, cancer therapy
- MeSH terms
- Bromodomain Containing Proteins, Animals, Antineoplastic Agents, DNA-Binding Proteins, Dose-Response Relationship, Drug, Female, Humans, Mice, Transgenic, Nuclear Proteins, Peptide Hydrolases, RNA Polymerase II, Time Factors, Transcription Factors, Transfection, Gene Expression Regulation, Leukemic, Mice, SCID, Mice, Inbred NOD, Cell Cycle Proteins, Jurkat Cells, Xenograft Model Antitumor Assays, Cyclin-Dependent Kinase 9, Ubiquitin-Protein Ligases, HCT116 Cells, Multiprotein Complexes, Adaptor Proteins, Signal Transducing, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Protein Stability, HEK293 Cells, Proteolysis, Transcription Elongation, Genetic
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
