ArticleProceedings of the National Academy of Sciences of the United States of America2018
Deubiquitinating enzyme USP3 controls CHK1 chromatin association and activation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed.
- USP3 promotes DNA damage response and chemotherapy resistance through stabilizing and deubiquitinating SMARCA5 in prostate cancer.Cell death & disease · 2024Article
- USP3: Key deubiquitylation enzyme in human diseases.Cancer science · 2024Review
- Ubiquitin specific peptidase 3: an emerging deubiquitinase that regulates physiology and diseases.Cell death discovery · 2024Review
- USP3 plays a critical role in the induction of innate immune tolerance.EMBO reports · 2023Article
- Deubiquitinases in cancer.Nature reviews. Cancer · 2023Review
- BRD7 suppresses tumor chemosensitivity to CHK1 inhibitors by inhibiting USP1-mediated deubiquitination of CHK1.Cell death discovery · 2023Article
- Ubiquitin-specific protease 3 facilitates cell proliferation by deubiquitinating pyruvate kinase L/R in gallbladder cancer.Laboratory investigation; a journal of technical methods and pathology · 2022Article
- Deubiquitinase OTUD6A promotes breast cancer progression by increasing TopBP1 stability and rendering tumor cells resistant to DNA-damaging therapy.Cell death and differentiation · 2022Article
- Chk1 Inhibition Hinders the Restoration of H3.1K56 and H3.3K56 Acetylation and Reprograms Gene Transcription After DNA Damage Repair.Frontiers in oncology · 2022Article
- A Catalytically Independent Function of Human DNA Polymerase Kappa Controls the Stability and Abundance of Checkpoint Kinase 1.Molecular and cellular biology · 2021Article
- Ubiquitin-Specific Proteases: Players in Cancer Cellular Processes.Pharmaceuticals (Basel, Switzerland) · 2021Review
- An ALYREF-MYCN coactivator complex drives neuroblastoma tumorigenesis through effects on USP3 and MYCN stability.Nature communications · 2021Article
- Role of deubiquitinating enzymes in DNA double-strand break repair.Journal of Zhejiang University. Science. B · 2021Review
- Molecular Mechanisms of Treatment Resistance in Glioblastoma.International journal of molecular sciences · 2020Review
- Review
- Ubiquitination of the DNA-damage checkpoint kinase CHK1 by TRAF4 is required for CHK1 activation.Journal of hematology & oncology · 2020Article
- USP3 promotes breast cancer cell proliferation by deubiquitinating KLF5.The Journal of biological chemistry · 2019Article
- Basal CHK1 activity safeguards its stability to maintain intrinsic S-phase checkpoint functions.The Journal of cell biology · 2019Article
- Ubiquitin-specific protease 3 promotes cell migration and invasion by interacting with and deubiquitinating SUZ12 in gastric cancer.Journal of experimental & clinical cancer research : CR · 2019Article
- The role of ubiquitin-specific peptidases in cancer progression.Journal of biomedical science · 2019Review
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Authors and funding
2 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Checkpoint kinase 1 (CHK1), a Ser/Thr protein kinase, is modified by the K63-linked ubiquitin chain in response to genotoxic stress, which promotes its nuclear localization, chromatin association, and activation. Interestingly, this bulky modification is linked to a critical residue, K132, at the kinase active site. It is unclear how this modification affects the kinase activity and how it is removed to enable the release of CHK1 from chromatin. Herein, we show that the K63-linked ubiquitin chain at CHK1's K132 residue has an inhibitory effect on the kinase activity. Furthermore, we demonstrate that this modification can be removed by ubiquitin-specific protease 3 (USP3), a deubiquitinating enzyme that targets K63-linked ubiquitin chains. Wild-type USP3, but not the catalytically defective or nuclear localization sequence-deficient mutants, reduced CHK1 K63-linked ubiquitination. Conversely, USP3 knockdown elevated K63-linked ubiquitination of the kinase, leading to prolonged CHK1 chromatin association and phosphorylation. Paradoxically, by removing the bulky ubiquitin chain at the active site, USP3 also increased the accessibility of CHK1 to its substrates. Thus, our findings on the dual roles of USP3 (namely, one to release CHK1 from the chromatin and the other to open up the active site) provide further insights into the regulation of CHK1 following DNA damage.
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