Role for KAP1 Serine 824 Phosphorylation and Sumoylation/Desumoylation Switch in Regulating KAP1-mediated Transcriptional Repression
Open accessAbstract
As a multifunctional protein, KRAB domain-associated protein 1 (KAP1) is reportedly subjected to multiple protein posttranslational modifications, including phosphorylation and sumoylation. However, gaps exist in our knowledge of how KAP1 phosphorylation cross-talks with KAP1 sumoylation and what the biological consequence is. Here, we show that doxorubicin (Dox) treatment induces KAP1 phosphorylation at Ser-824 via an ataxia telangiectasia mutated (ATM)-dependent manner, correlating with the transcriptional de-repression of p21WAF1/CIP1 and Gadd45alpha. A S824A substitution of KAP1, which ablates the ATM-induced phosphorylation, results in an increase of KAP1 sumoylation and repression of p21 transcription in Dox-treated cells. By contrast, a S824D mutation of KAP1, which mimics constitutive phosphorylation of KAP1, leads to a decrease of KAP1 sumoylation and stimulation of p21 transcription before the exposure of Dox. We further provide evidence that SENP1 deSUMOylase is involved in activating basal, but not Dox-induced, KAP1 Ser-824 phosphorylation, rendering a stimulation of p21 and Gadd45alpha transcription. Moreover, KAP1 and differential sumoylation of KAP1 were also demonstrated to fine-tune the transcription of three additional KAP1-targeted genes, including Bax, Puma, and Noxa. Taken together, our results suggest a novel role for ATM that selectively stimulates KAP1 Ser-824 phosphorylation to repress its sumoylation, leading to the de-repression of expression of a subset of genes involved in promoting cell cycle control and apoptosis in response to genotoxic stresses.
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Post-translational modification of KAP1 plays a critical role in determining which cellular context the protein will function in.
“post-translational modification of KAP1 plays a critical role in determining which cellular context the protein will function in; for example sumoylated KAP1 promotes regulation of gene expression, while phosphorylated KAP1 promotes DNA repair41,42.”
From SIRT6 represses LINE1 retrotransposons by ribosylating KAP1 but this repression fails with stress and age (2014) · cites this paper as [41]
The Discussion (page not available in our copy) supports the general point that KAP1 phosphorylation and sumoylation affect its function: sumoylation is linked to transcriptional repression, while phosphorylation after DNA damage reduces sumoylation and relieves repression. It also reports phosphorylated KAP1 at DNA lesions with damage-response factors, but does not establish the citing sentence’s stronger example that phosphorylated KAP1 promotes DNA repair. (LLM, conf=0.84)
Experimental — accuracy not yet measuredSIRT6 co-occupies approximately 10% of KAP1-bound promoters.
“analysis of promoter arrays41,42 showed that SIRT6 only co-occupies approximately 10% of KAP1 bound promoters”
From SIRT6 represses LINE1 retrotransposons by ribosylating KAP1 but this repression fails with stress and age (2014) · cites this paper as [41]
The introduction describes KAP1 as a transcriptional corepressor, and the Discussion examines its phosphorylation and desumoylation. Searches for SIRT6, promoter-array co-occupancy, and the approximately 10% figure found no passage addressing the claimed overlap. (LLM, conf=0.76)
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- Authors
- Li, X., Lee, Y.-K., Jeng, J.-C., Yen, Y., Schultz, D. C., Shih, H.-M., & Ann, D. K.
- Affiliations
- University of Southern California (US)
- Institute of Biomedical Sciences, Academia Sinica (TW)
- City Of Hope National Medical Center (US)
- The Wistar Institute (US)
- Corresponding author
- Ann, David K.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2007-12
- Volume
- 282
- Issue
- 50
- Pages
- 36177-36189
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2098646008
- Cited by
- 168
- References
- 46
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 3 · 2023: 13 · 2022: 6 · 2021: 4 · 2020: 6 · 2019: 5 · 2018: 14 · 2017: 13 · 2016: 13 · 2015: 12 · 2014: 13 · 2013: 9 · 2012: 20
- FWCI
- 2.92
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- University of Southern California
- National Health Research Institutes
- University of California, Davis
- National Institute of Dental and Craniofacial Research (R01 DE 10742, DE 14183, R01DE010742, R01DE014183)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- KAP1, SUMOylation, deSUMOylation, ATM, doxorubicin, p21, GADD45A, SENP1, transcriptional repression, apoptosis-related genes, Bax, PUMA, Noxa, cell cycle regulation, genotoxic stress, post-translational modification
- MeSH terms
- Tripartite Motif-Containing Protein 28, GADD45 Proteins, Antibiotics, Antineoplastic, Cell Cycle, Cell Line, Cysteine Endopeptidases, DNA Damage, DNA-Binding Proteins, Doxorubicin, Humans, Nuclear Proteins, Endopeptidases, Phosphorylation, Proto-Oncogene Proteins, Repressor Proteins, Serine, Transcription, Genetic, Apoptosis, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Proto-Oncogene Proteins c-bcl-2, Mutation, Missense, Tumor Suppressor Proteins, SUMO-1 Protein, Cyclin-Dependent Kinase Inhibitor p21, Apoptosis Regulatory Proteins, bcl-2-Associated X Protein, Ataxia Telangiectasia Mutated Proteins
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