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The KAP1 Corepressor Functions To Coordinate the Assembly of De Novo HP1-Demarcated Microenvironments of Heterochromatin Required for KRAB Zinc Finger Protein-Mediated Transcriptional Repression
Open accessAbstract
KAP1/TIF1beta is proposed to be a universal corepressor protein for the KRAB zinc finger protein (KRAB-zfp) superfamily of transcriptional repressors. To characterize the role of KAP1 and KAP1-interacting proteins in transcriptional repression, we investigated the regulation of stably integrated reporter transgenes by hormone-responsive KRAB and KAP1 repressor proteins. Here, we demonstrate that depletion of endogenous KAP1 levels by small interfering RNA (siRNA) significantly inhibited KRAB-mediated transcriptional repression of a chromatin template. Similarly, reduction in cellular levels of HP1alpha/beta/gamma and SETDB1 by siRNA attenuated KRAB-KAP1 repression. We also found that direct tethering of KAP1 to DNA was sufficient to repress transcription of an integrated transgene. This activity is absolutely dependent upon the interaction of KAP1 with HP1 and on an intact PHD finger and bromodomain of KAP1, suggesting that these domains function cooperatively in transcriptional corepression. The achievement of the repressed state by wild-type KAP1 involves decreased recruitment of RNA polymerase II, reduced levels of histone H3 K9 acetylation and H3K4 methylation, an increase in histone occupancy, enrichment of trimethyl histone H3K9, H3K36, and histone H4K20, and HP1 deposition at proximal regulatory sequences of the transgene. A KAP1 protein containing a mutation of the HP1 binding domain failed to induce any change in the histone modifications associated with DNA sequence…
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“KAP1 has been reported to induce silencing of endogenous retroelements31 in part by coordinating the assembly of a HP1α-SETDB1 dependent co-repressor complex32.”
From SIRT6 represses LINE1 retrotransposons by ribosylating KAP1 but this repression fails with stress and age (2014) · cites this paper as [32]
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Schultz, D. C., Ayyanathan, K., Negorev, D., Maul, G. G., & Rauscher, F. J. (2002) · Genes & Development · doi:10.1101/gad.973302 · Cited by 1,313
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Lepage, S. I. M. (2012) · cIRcle (University of British Columbia) · doi:10.14288/1.0072744
“The histone code hypothesis suggests that post-translational modifications work in a combinatorial and/or sequential fashion that can be read by proteins and interpreted into a variety of downstream effects (Strahl and Allis, 2000).”
BackgroundJiang, Y. (2009) · The Journal of the American Medical Association (JAMA) Network (American Medical Association) · doi:10.13028/a1cy-7882
“Depletion of Setdb1 or HP1 proteins attenuated KAP1/KRAB-zfp mediated transcriptional repression (Sripathy et al., 2006). iii) mSin3/HDAC1-2 corepressor complex: Setdb1 interacts with mSin3 via its N-terminal Tudor domain (Yang et al., 2003).”
BackgroundResultInfluentialThe regulation of preadipocyte differentiation by glucocorticoids
Tomlinson, J. J. (2007) · uO Research (University of Ottawa) · doi:10.20381/ruor-13103
Metadata
- Authors
- Sripathy, S. P., Stevens, J., & Schultz, D. C.
- Affiliations
- Case Comprehensive Cancer Center (US)
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2006-11-01
- Volume
- 26
- Issue
- 22
- Pages
- 8623-8638
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC1636786
- OpenAlex
- W2105073128
- Cited by
- 323
- References
- 70
- Citations by year
- 2026: 9 · 2025: 10 · 2024: 20 · 2023: 15 · 2022: 14 · 2021: 21 · 2020: 24 · 2019: 14 · 2018: 14 · 2017: 14 · 2016: 15 · 2015: 19 · 2014: 13 · 2013: 12 · 2012: 20
- FWCI
- 6.11
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Case Comprehensive Cancer Center, Case Western Reserve University
- National Cancer Institute (K01CA099093, CA-99093)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- KRAB zinc finger proteins, transcriptional repression, heterochromatin, HP1 proteins, SETDB1, PHD finger, bromodomain, histone modifications, H3K9 trimethylation, H3K4 methylation, nuclear compartmentalization, chromatin templates, RNA polymerase II recruitment
- MeSH terms
- Tripartite Motif-Containing Protein 28, Chromobox Protein Homolog 5, Cell Line, Chromatin, DNA-Binding Proteins, Heterochromatin, Histones, Hormones, Humans, Histone-Lysine N-Methyltransferase, Protein Methyltransferases, Repressor Proteins, RNA Polymerase II, Transcription Factors, Transcription, Genetic, Transfection, Genes, Reporter, Integrases, Saccharomyces cerevisiae Proteins, RNA, Small Interfering
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